VHS, ENTH and ANTH domain superfamily; This superfamily is composed of proteins containing a VHS, CID, ENTH, or ANTH domain. The VHS domain is present in Vps27 (Vacuolar Protein Sorting), Hrs (Hepatocyte growth factor-regulated tyrosine kinase substrate) and STAM (Signal Transducing Adaptor Molecule). It is located at the N-termini of proteins involved in intracellular membrane trafficking. The CTD-Interacting Domain (CID) is present in several RNA-processing factors and binds tightly to the carboxy-terminal domain (CTD) of RNA polymerase II (RNAP II or Pol II). The epsin N-terminal homology (ENTH) domain is an evolutionarily conserved protein module found primarily in proteins that participate in clathrin-mediated endocytosis. A set of proteins previously designated as harboring an ENTH domain in fact contains a highly similar, yet unique module referred to as an AP180 N-Terminal Homology (ANTH) domain. VHS, ENTH, and ANTH domains are structurally similar and are composed of a superhelix of eight alpha helices. ENTH and ANTH (E/ANTH) domains bind both inositol phospholipids and proteins and contribute to the nucleation and formation of clathrin coats on membranes. ENTH domains also function in the development of membrane curvature through lipid remodeling during the formation of clathrin-coated vesicles. E/ANTH domain-bearing proteins have recently been shown to function with adaptor protein-1 and GGA adaptors at the Trans-Golgi Network, which suggests that E/ANTH domains are universal components of the machinery for clathrin-mediated membrane budding.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2071133334  421 KFEDLLRHITPEKYKIAEAMIYCIDHAEAAEEIIECIGEAIAisEAPLYKKIARLYLISDILHNCSVKVanASYFRKGFQ 500
Cdd:smart00582   1 AFEQKLESLNNSQESIQTLTKWAIEHASHAKEIVELWEKYIK--KAPVPRKLPLLYLLDSIVQNSKRKY--GSEFGDELG 76

                           90       100       110       120       130
                   ....*....|....*....|....*....|....*....|....*....|....*.
gi 2071133334  501 NKLPDIFKDLHEIFQgidgrlraEQFKQRVVSCFRAWEDWAIYPSEFLIKLQNLFL 556
Cdd:smart00582  77 PVFQDALRRVLGAAP--------EELKKKIRRLLNIWEERGIFPPEVLRPLREKLN 124

domain present in proteins, which are involved in regulation of nuclear pre-mRNA;

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2071133334  421 KFEDLLRHITPEKYKIAEAMIYCIDHAEAAEEIIECIGEAIAisEAPLYKKIARLYLISDILHNCSVKVanASYFRKGFQ 500
Cdd:smart00582   1 AFEQKLESLNNSQESIQTLTKWAIEHASHAKEIVELWEKYIK--KAPVPRKLPLLYLLDSIVQNSKRKY--GSEFGDELG 76

                           90       100       110       120       130
                   ....*....|....*....|....*....|....*....|....*....|....*.
gi 2071133334  501 NKLPDIFKDLHEIFQgidgrlraEQFKQRVVSCFRAWEDWAIYPSEFLIKLQNLFL 556
Cdd:smart00582  77 PVFQDALRRVLGAAP--------EELKKKIRRLLNIWEERGIFPPEVLRPLREKLN 124

RNA recognition motif;

                           10        20        30        40        50        60        70
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 2071133334  156 NLYLGNLNPKMTEQQLCEVFGRFGPLASVKIMwprSDEERARGRNCGFVAFMNRKDGERAMKNLNGKDVMSFEMKL 231
Cdd:smart00360   1 TLFVGNLPPDTTEEELRELFSKFGKVESVRLV---RDKETGKSKGFAFVEFESEEDAEKALEALNGKELDGRPLKV 73

RNA recognition motif (RRM) domain [Translation, ribosomal structure and biogenesis];

                          10        20        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|..
gi 2071133334 154 TTNLYLGNLNPKMTEQQLCEVFGRFGPLASVKIMwprSDEERARGRNCGFVAFMNRKDGERAMKNLNGKDVM 225
Cdd:COG0724     1 SMKIYVGNLPYSVTEEDLRELFSEYGEVTSVKLI---TDRETGRSRGFGFVEMPDDEEAQAAIEALNGAELM 69

RNA recognition motif. (a.k.a. RRM, RBD, or RNP domain); The RRM motif is probably diagnostic of an RNA binding protein. RRMs are found in a variety of RNA binding proteins, including various hnRNP proteins, proteins implicated in regulation of alternative splicing, and protein components of snRNPs. The motif also appears in a few single stranded DNA binding proteins. The RRM structure consists of four strands and two helices arranged in an alpha/beta sandwich, with a third helix present during RNA binding in some cases The C-terminal beta strand (4th strand) and final helix are hard to align and have been omitted in the SEED alignment The LA proteins have an N terminal rrm which is included in the seed. There is a second region towards the C terminus that has some features characteriztic of a rrm but does not appear to have the important structural core of a rrm. The LA proteins are one of the main autoantigens in Systemic lupus erythematosus (SLE), an autoimmune disease.

                          10        20        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....
gi 2071133334 157 LYLGNLNPKMTEQQLCEVFGRFGPLASVKIMwprsDEERARGRNCGFVAFMNRKDGERAMKNLNGKDVMSFEMK 230
Cdd:pfam00076   1 LFVGNLPPDTTEEDLKDLFSKFGPIKSIRLV----RDETGRSKGFAFVEFEDEEDAEKAIEALNGKELGGRELK 70

CID (CTD-Interacting Domain) of Regulation of nuclear pre-mRNA domain-containing proteins; This family is composed of Regulation of nuclear pre-mRNA domain-containing proteins 1A (RPRD1A), 1B (RPRD1B), 2 (RPRD2), yeast Rtt103, and similar proteins. RPRD1A, RPRD1B, and RPRD2 are CID (CTD-Interacting Domain) containing proteins that co-purify with RNA polymerase (Pol) II (RNAP II) and three other RNAP II-associated proteins, RPAP2, GRINL1A and RECQL5, but not with the Mediator complex. Yeast transcription termination factor Rtt103 is a CID containing protein that functions in DNA damage response. CID binds tightly to the carboxy-terminal domain (CTD) of RNAP II. During transcription, RNAP II synthesizes eukaryotic messenger RNA. Transcription is coupled to RNA processing through the CTD, which consists of up to 52 repeats of the sequence Tyr1-Ser2-Pro3-Thr4-Ser5-Pro6-Ser7. CID contains eight alpha-helices in a right-handed superhelical arrangement, which closely resembles that of the VHS domains and ARM (Armadillo) repeat proteins, except for its two amino-terminal helices.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2071133334 419 RDKFEDLLRHITPEKYKIAEAMIYCIDHAEAAEEIIECIGEAIaiSEAPLYKKIARLYLISDILHNCSVKvaNASYFRKG 498
Cdd:cd16981     1 EEALEKKLRSLNNTQQSIQTLSLWCLFHKKHAKQIVKIWLKEL--KKAKPERKLTLLYLANDVLQNSRRK--GAPEFVEA 76

                          90       100       110       120       130
                  ....*....|....*....|....*....|....*....|....*....|....*.
gi 2071133334 499 FQNKLPDIFKDlheIFQGIDGRLRaeqfkQRVVSCFRAWEDWAIYPSEFLIKLQNL 554
Cdd:cd16981    77 FKKVLPEALAL---VRSEGDESVR-----KKVLRVLNIWEERNVFGSEFLAELRAI 124

domain present in proteins, which are involved in regulation of nuclear pre-mRNA;

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2071133334  421 KFEDLLRHITPEKYKIAEAMIYCIDHAEAAEEIIECIGEAIAisEAPLYKKIARLYLISDILHNCSVKVanASYFRKGFQ 500
Cdd:smart00582   1 AFEQKLESLNNSQESIQTLTKWAIEHASHAKEIVELWEKYIK--KAPVPRKLPLLYLLDSIVQNSKRKY--GSEFGDELG 76

                           90       100       110       120       130
                   ....*....|....*....|....*....|....*....|....*....|....*.
gi 2071133334  501 NKLPDIFKDLHEIFQgidgrlraEQFKQRVVSCFRAWEDWAIYPSEFLIKLQNLFL 556
Cdd:smart00582  77 PVFQDALRRVLGAAP--------EELKKKIRRLLNIWEERGIFPPEVLRPLREKLN 124

RNA recognition motif;

                           10        20        30        40        50        60        70
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 2071133334  156 NLYLGNLNPKMTEQQLCEVFGRFGPLASVKIMwprSDEERARGRNCGFVAFMNRKDGERAMKNLNGKDVMSFEMKL 231
Cdd:smart00360   1 TLFVGNLPPDTTEEELRELFSKFGKVESVRLV---RDKETGKSKGFAFVEFESEEDAEKALEALNGKELDGRPLKV 73

RNA recognition motif (RRM) superfamily; RRM, also known as RBD (RNA binding domain) or RNP (ribonucleoprotein domain), is a highly abundant domain in eukaryotes found in proteins involved in post-transcriptional gene expression processes including mRNA and rRNA processing, RNA export, and RNA stability. This domain is 90 amino acids in length and consists of a four-stranded beta-sheet packed against two alpha-helices. RRM usually interacts with ssRNA, but is also known to interact with ssDNA as well as proteins. RRM binds a variable number of nucleotides, ranging from two to eight. The active site includes three aromatic side-chains located within the conserved RNP1 and RNP2 motifs of the domain. The RRM domain is found in a variety heterogeneous nuclear ribonucleoproteins (hnRNPs), proteins implicated in regulation of alternative splicing, and protein components of small nuclear ribonucleoproteins (snRNPs).

                          10        20        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 2071133334 157 LYLGNLNPKMTEQQLCEVFGRFGPLASVKIMWPRSDeeraRGRNCGFVAFMNRKDGERAMKNLNGKDVMSFEMKL 231
Cdd:cd00590     1 LFVGNLPPDTTEEDLRELFSKFGEVVSVRIVRDRDG----KSKGFAFVEFESPEDAEKALEALNGTELGGRPLKV 71

CID domain; This domain binds to the phosphorylated C-terminal domain (CTD) of RNA polymerase II. This domain is known as the CTD-interacting domain (CID).

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2071133334 420 DKFEDLLRHITPEKYKIAEAMIYCIDHAEAAEEIIECIGEAIaiSEAPLYKKIARLYLISDILHNCSVKvaNASYFRKGF 499
Cdd:pfam04818   1 EALEKKLSSLNNSQESIQTLSKWILFHRKHAKAIVEVWEKYL--KKAKPEKKLHLLYLANDVLQNSRKK--GKSEFADAF 76

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|....*....
gi 2071133334 500 QNKLPDIFKDLheifqgidGRLRAEQFKQRVVSCFRAWEDWAIYPSEFL 548
Cdd:pfam04818  77 EPVLPEAFASA--------YKKCDEKLKKKLERLLNIWEERNVFSPEVI 117

RNA recognition motif 3 (RRM3) found in yeast negative growth regulatory protein NGR1 (RBP1), yeast protein NAM8 and similar proteins; This subfamily corresponds to the RRM3 of NGR1 and NAM8. NGR1, also termed RNA-binding protein RBP1, is a putative glucose-repressible protein that binds both RNA and single-stranded DNA (ssDNA) in yeast. It may function in regulating cell growth in early log phase, possibly through its participation in RNA metabolism. NGR1 contains two RNA recognition motifs (RRMs), also termed RBDs (RNA binding domains) or RNPs (ribonucleoprotein domains), followed by a glutamine-rich stretch that may be involved in transcriptional activity. In addition, NGR1 has an asparagine-rich region near the carboxyl terminus which also harbors a methionine-rich region. The family also includes protein NAM8, which is a putative RNA-binding protein that acts as a suppressor of mitochondrial splicing deficiencies when overexpressed in yeast. It may be a non-essential component of the mitochondrial splicing machinery. Like NGR1, NAM8 contains two RRMs.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2071133334 155 TNLYLGNLNPKMTEQQLCEVFGRFGPLASVKImwprsdeerARGRNCGFVAFMNRKDGERAMKNLNGKDVMSFEMKLGWG 234
Cdd:cd12346     2 TTVFVGGLDPNVTEEDLRVLFGPFGEIVYVKI---------PPGKGCGFVQFVNRASAEAAIQKLQGTPIGGSRIRLSWG 72

RNA recognition motif 2 (RRM2) found in yeast nuclear and cytoplasmic polyadenylated RNA-binding protein PUB1 and similar proteins; This subgroup corresponds to the RRM2 of yeast protein PUB1, also termed ARS consensus-binding protein ACBP-60, or poly uridylate-binding protein, or poly(U)-binding protein. PUB1 has been identified as both, a heterogeneous nuclear RNA-binding protein (hnRNP) and a cytoplasmic mRNA-binding protein (mRNP), which may be stably bound to a translationally inactive subpopulation of mRNAs within the cytoplasm. It is distributed in both, the nucleus and the cytoplasm, and binds to poly(A)+ RNA (mRNA or pre-mRNA). Although it is one of the major cellular proteins cross-linked by UV light to polyadenylated RNAs in vivo, PUB1 is nonessential for cell growth in yeast. PUB1 also binds to T-rich single stranded DNA (ssDNA). However, there is no strong evidence implicating PUB1 in the mechanism of DNA replication. PUB1 contains three RNA recognition motifs (RRMs), also termed RBDs (RNA binding domains) or RNPs (ribonucleoprotein domains), and a GAR motif (glycine and arginine rich stretch) that is located between RRM2 and RRM3.

                          10        20        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 2071133334 156 NLYLGNLNPKMTEQQLCEVFGRFGPLASVKIMWprsDEERARGRNCGFVAFMNRKDGERAMKNLNGKDVMSFEMKLGW 233
Cdd:cd12619     3 NIFVGDLSPEVTDAALFNAFSDFPSCSDARVMW---DQKTGRSRGYGFVSFRSQQDAQNAINSMNGKWLGSRPIRCNW 77

RNA recognition motif. (a.k.a. RRM, RBD, or RNP domain); The RRM motif is probably diagnostic of an RNA binding protein. RRMs are found in a variety of RNA binding proteins, including various hnRNP proteins, proteins implicated in regulation of alternative splicing, and protein components of snRNPs. The motif also appears in a few single stranded DNA binding proteins. The RRM structure consists of four strands and two helices arranged in an alpha/beta sandwich, with a third helix present during RNA binding in some cases The C-terminal beta strand (4th strand) and final helix are hard to align and have been omitted in the SEED alignment The LA proteins have an N terminal rrm which is included in the seed. There is a second region towards the C terminus that has some features characteriztic of a rrm but does not appear to have the important structural core of a rrm. The LA proteins are one of the main autoantigens in Systemic lupus erythematosus (SLE), an autoimmune disease.

                          10        20        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....
gi 2071133334 157 LYLGNLNPKMTEQQLCEVFGRFGPLASVKIMwprsDEERARGRNCGFVAFMNRKDGERAMKNLNGKDVMSFEMK 230
Cdd:pfam00076   1 LFVGNLPPDTTEEDLKDLFSKFGPIKSIRLV----RDETGRSKGFAFVEFEDEEDAEKAIEALNGKELGGRELK 70

RNA recognition motif (RRM) found in eukaryotic RNA-binding protein 18 and similar proteins; This subfamily corresponds to the RRM of RBM18, a putative RNA-binding protein containing a well-conserved RNA recognition motif (RRM), also termed RBD (RNA binding domain) or RNP (ribonucleoprotein domain). The biological role of RBM18 remains unclear.

                          10        20        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|.
gi 2071133334 156 NLYLGNLNPKMTEQQLCEVFGRFGPLASVKIMWPRSDEERARGRNCGFVAFMNRKDGERAMKNLNGKDVMS 226
Cdd:cd12355     1 RLWIGNLDPRLTEYHLLKLLSKYGKIKKFDFLFHKTGPLKGQPRGYCFVTFETKEEAEKAIECLNGKLALG 71

RNA recognition motif 2 (RRM2) found in Nicotiana sylvestris chloroplastic 33 kDa ribonucleoprotein (NsCP33) and similar proteins; The family includes NsCP33, Arabidopsis thaliana chloroplastic 31 kDa ribonucleoprotein (CP31A) and mitochondrial glycine-rich RNA-binding protein 2 (AtGR-RBP2). NsCP33 may be involved in splicing and/or processing of chloroplast RNA's. AtCP31A, also called RNA-binding protein 1/2/3 (AtRBP33), or RNA-binding protein CP31A, or RNA-binding protein RNP-T, or RNA-binding protein cp31, is required for specific RNA editing events in chloroplasts and stabilizes specific chloroplast mRNAs, as well as for normal chloroplast development under cold stress conditions by stabilizing transcripts of numerous mRNAs under these conditions. CP31A may modulate telomere replication through RNA binding domains. AtGR-RBP2, also called AtRBG2, or glycine-rich protein 2 (AtGRP2), or mitochondrial RNA-binding protein 1a (At-mRBP1a), plays a role in RNA transcription or processing during stress. It binds RNAs and DNAs sequence with a preference to single-stranded nucleic acids. AtGR-RBP2 displays strong affinity to poly(U) sequence. It exerts cold and freezing tolerance, probably by exhibiting an RNA chaperone activity during the cold and freezing adaptation process. Some members in this family contain two RNA recognition motifs (RRMs), also termed RBDs (RNA binding domains) or RNPs (ribonucleoprotein domains). The model corresponds to the second RRM motif.

                          10        20        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2071133334 156 NLYLGNLNPKMTEQQLCEVFGRFGPLASVKIMwprSDEERARGRNCGFVAFMNRKDGERAMKNLNGKDVM 225
Cdd:cd21608     1 KLYVGNLSWDTTEDDLRDLFSEFGEVESAKVI---TDRETGRSRGFGFVTFSTAEAAEAAIDALNGKELD 67

RNA recognition motif (RRM) found in the Aly/REF family; This subfamily corresponds to the RRM of Aly/REF family which includes THO complex subunit 4 (THOC4, also termed Aly/REF), S6K1 Aly/REF-like target (SKAR, also termed PDIP3 or PDIP46) and similar proteins. THOC4 is an mRNA transporter protein with a well conserved RNA recognition motif (RRM), also termed RBD (RNA binding domain) or RNP (ribonucleoprotein domain). It is involved in RNA transportation from the nucleus, and was initially identified as a transcription coactivator of LEF-1 and AML-1 for the TCRalpha enhancer function. In addition, THOC4 specifically binds to rhesus (RH) promoter in erythroid, and might be a novel transcription cofactor for erythroid-specific genes. SKAR shows high sequence homology with THOC4 and possesses one RRM as well. SKAR is widely expressed and localizes to the nucleus. It may be a critical player in the function of S6K1 in cell and organism growth control by binding the activated, hyperphosphorylated form of S6K1 but not S6K2. Furthermore, SKAR functions as a protein partner of the p50 subunit of DNA polymerase delta. In addition, SKAR may have particular importance in pancreatic beta cell size determination and insulin secretion.

                          10        20        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 2071133334 155 TNLYLGNLNPKMTEQQLCEVFGRFGPLASVKIMWPRSDeeRARGrnCGFVAFMNRKDGERAMKNLNGKDVMSFEMKL 231
Cdd:cd12418     1 TRVRVSNLHPDVTEEDLRELFGRVGPVKSVKINYDRSG--RSTG--TAYVVFERPEDAEKAIKQFDGVLLDGQPMKV 73

RNA recognition motif (RRM) found in eukaryotic translation initiation factor 3 subunit G (eIF-3G) and similar proteins; This subfamily corresponds to the RRM of eIF-3G and similar proteins. eIF-3G, also termed eIF-3 subunit 4, or eIF-3-delta, or eIF3-p42, or eIF3-p44, is the RNA-binding subunit of eIF3, a large multisubunit complex that plays a central role in the initiation of translation by binding to the 40 S ribosomal subunit and promoting the binding of methionyl-tRNAi and mRNA. eIF-3G binds 18 S rRNA and beta-globin mRNA, and therefore appears to be a nonspecific RNA-binding protein. eIF-3G is one of the cytosolic targets and interacts with mature apoptosis-inducing factor (AIF). eIF-3G contains one RNA recognition motif (RRM), also termed RBD (RNA binding domain) or RNP (ribonucleoprotein domain). This family also includes yeast eIF3-p33, a homolog of vertebrate eIF-3G, plays an important role in the initiation phase of protein synthesis in yeast. It binds both, mRNA and rRNA, fragments due to an RRM near its C-terminus.

                          10        20        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|...
gi 2071133334 161 NLNPKMTEQQLCEVFGRFGPLASVKImwPRsDEERARGRNCGFVAFMNRKDGERAMKNLNGKDVMSFEMKLGW 233
Cdd:cd12408     6 NLSEDATEEDLRELFRPFGPISRVYL--AK-DKETGQSKGFAFVTFETREDAERAIEKLNGFGYDNLILSVEW 75

RNA recognition motif 4 (RRM4) found in type I polyadenylate-binding proteins; This subfamily corresponds to the RRM4 of type I poly(A)-binding proteins (PABPs), highly conserved proteins that bind to the poly(A) tail present at the 3' ends of most eukaryotic mRNAs. They have been implicated in theThe CD corresponds to the RRM. regulation of poly(A) tail length during the polyadenylation reaction, translation initiation, mRNA stabilization by influencing the rate of deadenylation and inhibition of mRNA decapping. The family represents type I polyadenylate-binding proteins (PABPs), including polyadenylate-binding protein 1 (PABP-1 or PABPC1), polyadenylate-binding protein 3 (PABP-3 or PABPC3), polyadenylate-binding protein 4 (PABP-4 or APP-1 or iPABP), polyadenylate-binding protein 5 (PABP-5 or PABPC5), polyadenylate-binding protein 1-like (PABP-1-like or PABPC1L), polyadenylate-binding protein 1-like 2 (PABPC1L2 or RBM32), polyadenylate-binding protein 4-like (PABP-4-like or PABPC4L), yeast polyadenylate-binding protein, cytoplasmic and nuclear (PABP or ACBP-67), and similar proteins. PABP-1 is an ubiquitously expressed multifunctional protein that may play a role in 3' end formation of mRNA, translation initiation, mRNA stabilization, protection of poly(A) from nuclease activity, mRNA deadenylation, inhibition of mRNA decapping, and mRNP maturation. Although PABP-1 is thought to be a cytoplasmic protein, it is also found in the nucleus. PABP-1 may be involved in nucleocytoplasmic trafficking and utilization of mRNP particles. PABP-1 contains four copies of RNA recognition motifs (RRMs), also termed RBDs (RNA binding domains) or RNPs (ribonucleoprotein domains), a less well conserved linker region, and a proline-rich C-terminal conserved domain (CTD). PABP-3 is a testis-specific poly(A)-binding protein specifically expressed in round spermatids. It is mainly found in mammalian and may play an important role in the testis-specific regulation of mRNA homeostasis. PABP-3 shows significant sequence similarity to PABP-1. However, it binds to poly(A) with a lower affinity than PABP-1. Moreover, PABP-1 possesses an A-rich sequence in its 5'-UTR and allows binding of PABP and blockage of translation of its own mRNA. In contrast, PABP-3 lacks the A-rich sequence in its 5'-UTR. PABP-4 is an inducible poly(A)-binding protein (iPABP) that is primarily localized to the cytoplasm. It shows significant sequence similarity to PABP-1 as well. The RNA binding properties of PABP-1 and PABP-4 appear to be identical. PABP-5 is encoded by PABPC5 gene within the X-specific subinterval, and expressed in fetal brain and in a range of adult tissues in mammalian, such as ovary and testis. It may play an important role in germ cell development. Moreover, unlike other PABPs, PABP-5 contains only four RRMs, but lacks both the linker region and the CTD. PABP-1-like and PABP-1-like 2 are the orthologs of PABP-1. PABP-4-like is the ortholog of PABP-5. Their cellular functions remain unclear. The family also includes the yeast PABP, a conserved poly(A) binding protein containing poly(A) tails that can be attached to the 3'-ends of mRNAs. The yeast PABP and its homologs may play important roles in the initiation of translation and in mRNA decay. Like vertebrate PABP-1, the yeast PABP contains four RRMs, a linker region, and a proline-rich CTD as well. The first two RRMs are mainly responsible for specific binding to poly(A). The proline-rich region may be involved in protein-protein interactions.

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 2071133334 156 NLYLGNLNPKMTEQQLCEVFGRFGPLASVKIMwpRSDEERARGrnCGFVAFMNRKDGERAMKNLNGK 222
Cdd:cd12381     3 NLYVKNLDDTIDDEKLREEFSPFGTITSAKVM--TDEGGRSKG--FGFVCFSSPEEATKAVTEMNGR 65

RNA recognition motif 2 (RRM2) found in vertebrate RNA binding motif protein 15 (RBM15); This subgroup corresponds to the RRM2 of RBM15, also termed one-twenty two protein 1 (OTT1), conserved in eukaryotes, a novel mRNA export factor and component of the NXF1 pathway. It binds to NXF1 and serves as receptor for the RNA export element RTE. It also possesses mRNA export activity and can facilitate the access of DEAD-box protein DBP5 to mRNA at the nuclear pore complex (NPC). RBM15 belongs to the Spen (split end) protein family, which contain three N-terminal RNA recognition motifs (RRMs), also known as RBD (RNA binding domain) or RNP (ribonucleoprotein domain), and a C-terminal SPOC (Spen paralog and ortholog C-terminal) domain. This family also includes a RBM15-MKL1 (OTT-MAL) fusion protein that RBM15 is N-terminally fused to megakaryoblastic leukemia 1 protein (MKL1) at the C-terminus in a translocation involving chromosome 1 and 22, resulting in acute megakaryoblastic leukemia. The fusion protein could interact with the mRNA export machinery. Although it maintains the specific transactivator function of MKL1, the fusion protein cannot activate RTE-mediated mRNA expression and has lost the post-transcriptional activator function of RBM15. However, it has transdominant suppressor function contributing to its oncogenic properties.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2071133334 157 LYLGNLNPKMTEQQLCEVFGRFGPLASVKIMWPrsdeERARGRNCGFVAFMNRKDGERAMKNLNGKDVMSFEMKLGWGKA 236
Cdd:cd12555    10 LFLGNLDITVTENDLRRAFDRFGVITEVDIKRP----GRGQTSTYGFLKFENLDMAHRAKLAMSGKVIGRNPIKIGYGKA 85

                  .
gi 2071133334 237 V 237
Cdd:cd12555    86 T 86

polyadenylate binding protein, human types 1, 2, 3, 4 family; These eukaryotic proteins recognize the poly-A of mRNA and consists of four tandem RNA recognition domains at the N-terminus (rrm: pfam00076) followed by a PABP-specific domain (pfam00658) at the C-terminus. The protein is involved in the transport of mRNA's from the nucleus to the cytoplasm. There are four paralogs in Homo sapiens which are expressed in testis, platelets, broadly expressed and of unknown tissue range.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2071133334 149 TGDPSTTNLYLGNLNPKMTEQQLCEVFGRFGPLASVKIMwprsDEERARGRNCGFVAFMNRKDGERAMKNLNGK--DVMS 226
Cdd:TIGR01628 173 APLKKFTNLYVKNLDPSVNEDKLRELFAKFGEITSAAVM----KDGSGRSRGFAFVNFEKHEDAAKAVEEMNGKkiGLAK 248

                          90
                  ....*....|
gi 2071133334 227 FEMKLGWGKA 236
Cdd:TIGR01628 249 EGKKLYVGRA 258

polyadenylate binding protein, human types 1, 2, 3, 4 family; These eukaryotic proteins recognize the poly-A of mRNA and consists of four tandem RNA recognition domains at the N-terminus (rrm: pfam00076) followed by a PABP-specific domain (pfam00658) at the C-terminus. The protein is involved in the transport of mRNA's from the nucleus to the cytoplasm. There are four paralogs in Homo sapiens which are expressed in testis, platelets, broadly expressed and of unknown tissue range.

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 2071133334 156 NLYLGNLNPKMTEQQLCEVFGRFGPLASVKIMwpRSDEERARGrnCGFVAFMNRKDGERAMKNLNGK 222
Cdd:TIGR01628 287 NLYVKNLDDTVTDEKLRELFSECGEITSAKVM--LDEKGVSRG--FGFVCFSNPEEANRAVTEMHGR 349

CID (CTD-Interacting Domain) of Regulation of nuclear pre-mRNA domain-containing proteins; This family is composed of Regulation of nuclear pre-mRNA domain-containing proteins 1A (RPRD1A), 1B (RPRD1B), 2 (RPRD2), yeast Rtt103, and similar proteins. RPRD1A, RPRD1B, and RPRD2 are CID (CTD-Interacting Domain) containing proteins that co-purify with RNA polymerase (Pol) II (RNAP II) and three other RNAP II-associated proteins, RPAP2, GRINL1A and RECQL5, but not with the Mediator complex. Yeast transcription termination factor Rtt103 is a CID containing protein that functions in DNA damage response. CID binds tightly to the carboxy-terminal domain (CTD) of RNAP II. During transcription, RNAP II synthesizes eukaryotic messenger RNA. Transcription is coupled to RNA processing through the CTD, which consists of up to 52 repeats of the sequence Tyr1-Ser2-Pro3-Thr4-Ser5-Pro6-Ser7. CID contains eight alpha-helices in a right-handed superhelical arrangement, which closely resembles that of the VHS domains and ARM (Armadillo) repeat proteins, except for its two amino-terminal helices.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2071133334 419 RDKFEDLLRHITPEKYKIAEAMIYCIDHAEAAEEIIECIGEAIaiSEAPLYKKIARLYLISDILHNCSVKvaNASYFRKG 498
Cdd:cd16981     1 EEALEKKLRSLNNTQQSIQTLSLWCLFHKKHAKQIVKIWLKEL--KKAKPERKLTLLYLANDVLQNSRRK--GAPEFVEA 76

                          90       100       110       120       130
                  ....*....|....*....|....*....|....*....|....*....|....*.
gi 2071133334 499 FQNKLPDIFKDlheIFQGIDGRLRaeqfkQRVVSCFRAWEDWAIYPSEFLIKLQNL 554
Cdd:cd16981    77 FKKVLPEALAL---VRSEGDESVR-----KKVLRVLNIWEERNVFGSEFLAELRAI 124

RNA recognition motif 1 (RRM1) found in splicing factor 3B subunit 4 (SF3B4) and similar proteins; This subfamily corresponds to the RRM1 of SF3B4, also termed pre-mRNA-splicing factor SF3b 49 kDa (SF3b50), or spliceosome-associated protein 49 (SAP 49). SF3B4 a component of the multiprotein complex splicing factor 3b (SF3B), an integral part of the U2 small nuclear ribonucleoprotein (snRNP) and the U11/U12 di-snRNP. SF3B is essential for the accurate excision of introns from pre-messenger RNA, and is involved in the recognition of the pre-mRNA's branch site within the major and minor spliceosomes. SF3B4 functions to tether U2 snRNP with pre-mRNA at the branch site during spliceosome assembly. It is an evolutionarily highly conserved protein with orthologs across diverse species. SF3B4 contains two closely adjacent N-terminal RNA recognition motifs (RRMs), also termed RBDs (RNA binding domains) or RNPs (ribonucleoprotein domains). It binds directly to pre-mRNA and also interacts directly and highly specifically with another SF3B subunit called SAP 145.

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 2071133334 157 LYLGNLNPKMTEQQLCEVFGRFGPLASVKImwPRsDEERARGRNCGFVAFMNRKDGERAMKNLNG 221
Cdd:cd12334     1 VYVGNLDEKVTEELLWELFIQAGPVVNVHM--PK-DRVTQQHQGYGFVEFLSEEDADYAIKIMNM 62

RNA recognition motif 2 (RRM2) found in the Hu proteins family, Drosophila sex-lethal (SXL), and similar proteins; This subfamily corresponds to the RRM2 of Hu proteins and SXL. The Hu proteins family represents a group of RNA-binding proteins involved in diverse biological processes. Since the Hu proteins share high homology with the Drosophila embryonic lethal abnormal vision (ELAV) protein, the Hu family is sometimes referred to as the ELAV family. Drosophila ELAV is exclusively expressed in neurons and is required for the correct differentiation and survival of neurons in flies. The neuronal members of the Hu family include Hu-antigen B (HuB or ELAV-2 or Hel-N1), Hu-antigen C (HuC or ELAV-3 or PLE21), and Hu-antigen D (HuD or ELAV-4), which play important roles in neuronal differentiation, plasticity and memory. HuB is also expressed in gonads. Hu-antigen R (HuR or ELAV-1 or HuA) is the ubiquitously expressed Hu family member. It has a variety of biological functions mostly related to the regulation of cellular response to DNA damage and other types of stress. Hu proteins perform their cytoplasmic and nuclear molecular functions by coordinately regulating functionally related mRNAs. In the cytoplasm, Hu proteins recognize and bind to AU-rich RNA elements (AREs) in the 3' untranslated regions (UTRs) of certain target mRNAs, such as GAP-43, vascular epithelial growth factor (VEGF), the glucose transporter GLUT1, eotaxin and c-fos, and stabilize those ARE-containing mRNAs. They also bind and regulate the translation of some target mRNAs, such as neurofilament M, GLUT1, and p27. In the nucleus, Hu proteins function as regulators of polyadenylation and alternative splicing. Each Hu protein contains three RNA recognition motifs (RRMs), also termed RBDs (RNA binding domains) or RNPs (ribonucleoprotein domains). RRM1 and RRM2 may cooperate in binding to an ARE. RRM3 may help to maintain the stability of the RNA-protein complex, and might also bind to poly(A) tails or be involved in protein-protein interactions. Also included in this subfamily is the sex-lethal protein (SXL) from Drosophila melanogaster. SXL governs sexual differentiation and X chromosome dosage compensation in flies. It induces female-specific alternative splicing of the transformer (tra) pre-mRNA by binding to the tra uridine-rich polypyrimidine tract at the non-sex-specific 3' splice site during the sex-determination process. SXL binds also to its own pre-mRNA and promotes female-specific alternative splicing. SXL contains an N-terminal Gly/Asn-rich domain that may be responsible for the protein-protein interaction, and tandem RRMs that show high preference to bind single-stranded, uridine-rich target RNA transcripts.

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 2071133334 155 TNLYLGNLNPKMTEQQLCEVFGRFGPLASVKIMwprSDEERARGRNCGFVAFMNRKDGERAMKNLNG 221
Cdd:cd12376     1 ANLYVSGLPKTMTQKELEQLFSQYGRIITSRIL---RDQLTGVSRGVGFIRFDKRIEAEEAIKGLNG 64

RNA recognition motif (RRM) found in nuclear cap-binding protein subunit 2 (CBP20) and similar proteins; This subfamily corresponds to the RRM of CBP20, also termed nuclear cap-binding protein subunit 2 (NCBP2), or cell proliferation-inducing gene 55 protein, or NCBP-interacting protein 1 (NIP1). CBP20 is the small subunit of the nuclear cap binding complex (CBC), which is a conserved eukaryotic heterodimeric protein complex binding to 5'-capped polymerase II transcripts and plays a central role in the maturation of pre-mRNA and uracil-rich small nuclear RNA (U snRNA). CBP20 is most likely responsible for the binding of capped RNA. It contains an RNA recognition motif (RRM), also termed RBD (RNA binding domain) or RNP (ribonucleoprotein domain), and interacts with the second and third domains of CBP80, the large subunit of CBC.

                          10        20        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|...
gi 2071133334 157 LYLGNLNPKMTEQQLCEVFGRFGPLASVkIMwprsdeerarGRN------CG--FVAFMNRKDGERAMKNLNG 221
Cdd:cd12240     1 LYVGNLSFYTTEEQIYELFSKCGDIKRI-IM----------GLDkfkktpCGfcFVEYYSREDAENAVKYLNG 62

RNA recognition motif (RRM) found in transformer-2 protein homolog TRA2-alpha, TRA2-beta and similar proteins; This subfamily corresponds to the RRM of two mammalian homologs of Drosophila transformer-2 (Tra2), TRA2-alpha, TRA2-beta (also termed SFRS10), and similar proteins found in eukaryotes. TRA2-alpha is a 40-kDa serine/arginine-rich (SR) protein that specifically binds to gonadotropin-releasing hormone (GnRH) exonic splicing enhancer on exon 4 (ESE4) and is necessary for enhanced GnRH pre-mRNA splicing. It strongly stimulates GnRH intron A excision in a dose-dependent manner. In addition, TRA2-alpha can interact with either 9G8 or SRp30c, which may also be crucial for ESE-dependent GnRH pre-mRNA splicing. TRA2-beta is a serine/arginine-rich (SR) protein that controls the pre-mRNA alternative splicing of the calcitonin/calcitonin gene-related peptide (CGRP), the survival motor neuron 1 (SMN1) protein and the tau protein. Both, TRA2-alpha and TRA2-beta, contains a well conserved RNA recognition motif (RRM), also termed RBD (RNA binding domain) or RNP (ribonucleoprotein domain), flanked by the N- and C-terminal arginine/serine (RS)-rich regions.

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|....
gi 2071133334 161 NLNPKMTEQQLCEVFGRFGPLASVKIMWprsDEERARGRNCGFVAFMNRKDGERAMKNLNGKDV 224
Cdd:cd12363     8 GLSLYTTERDLREVFSRYGPIEKVQVVY---DQQTGRSRGFGFVYFESVEDAKEAKERLNGQEI 68

RNA recognition motif (RRM) found in cleavage stimulation factor subunit 2 (CSTF2), cleavage stimulation factor subunit 2 tau variant (CSTF2T) and similar proteins; This subgroup corresponds to the RRM domain of CSTF2, its tau variant and eukaryotic homologs. CSTF2, also termed cleavage stimulation factor 64 kDa subunit (CstF64), is the vertebrate conterpart of yeast mRNA 3'-end-processing protein RNA15. It is expressed in all somatic tissues and is one of three cleavage stimulatory factor (CstF) subunits required for polyadenylation. CstF64 contains an N-terminal RNA recognition motif (RRM), also known as RBD (RNA binding domain) or RNP (ribonucleoprotein domain), a CstF77-binding domain, a repeated MEARA helical region and a conserved C-terminal domain reported to bind the transcription factor PC-4. During polyadenylation, CstF interacts with the pre-mRNA through the RRM of CstF64 at U- or GU-rich sequences within 10 to 30 nucleotides downstream of the cleavage site. CSTF2T, also termed tauCstF64, is a paralog of the X-linked cleavage stimulation factor CstF64 protein that supports polyadenylation in most somatic cells. It is expressed during meiosis and subsequent haploid differentiation in a more limited set of tissues and cell types, largely in meiotic and postmeiotic male germ cells, and to a lesser extent in brain. The loss of CSTF2T will cause male infertility, as it is necessary for spermatogenesis and fertilization. Moreover, CSTF2T is required for expression of genes involved in morphological differentiation of spermatids, as well as for genes having products that function during interaction of motile spermatozoa with eggs. It promotes germ cell-specific patterns of polyadenylation by using its RRM to bind to different sequence elements downstream of polyadenylation sites than does CstF64.

                          10        20        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....
gi 2071133334 151 DPSTTNLYLGNLNPKMTEQQLCEVFGRFGPLASVKIMWprsDEERARGRNCGFVAFMNRKDGERAMKNLNGKDV 224
Cdd:cd12671     3 DRSLRSVFVGNIPYEATEEQLKDIFSEVGPVVSFRLVY---DRETGKPKGYGFCEYQDQETALSAMRNLNGYEL 73

RNA recognition motif 1 (RRM1) found in type I polyadenylate-binding proteins; This subfamily corresponds to the RRM1 of type I poly(A)-binding proteins (PABPs), highly conserved proteins that bind to the poly(A) tail present at the 3' ends of most eukaryotic mRNAs. They have been implicated in the regulation of poly(A) tail length during the polyadenylation reaction, translation initiation, mRNA stabilization by influencing the rate of deadenylation and inhibition of mRNA decapping. The family represents type I polyadenylate-binding proteins (PABPs), including polyadenylate-binding protein 1 (PABP-1 or PABPC1), polyadenylate-binding protein 3 (PABP-3 or PABPC3), polyadenylate-binding protein 4 (PABP-4 or APP-1 or iPABP), polyadenylate-binding protein 5 (PABP-5 or PABPC5), polyadenylate-binding protein 1-like (PABP-1-like or PABPC1L), polyadenylate-binding protein 1-like 2 (PABPC1L2 or RBM32), polyadenylate-binding protein 4-like (PABP-4-like or PABPC4L), yeast polyadenylate-binding protein, cytoplasmic and nuclear (PABP or ACBP-67), and similar proteins. PABP-1 is a ubiquitously expressed multifunctional protein that may play a role in 3' end formation of mRNA, translation initiation, mRNA stabilization, protection of poly(A) from nuclease activity, mRNA deadenylation, inhibition of mRNA decapping, and mRNP maturation. Although PABP-1 is thought to be a cytoplasmic protein, it is also found in the nucleus. PABP-1 may be involved in nucleocytoplasmic trafficking and utilization of mRNP particles. PABP-1 contains four copies of RNA recognition motifs (RRMs), also termed RBDs (RNA binding domains) or RNPs (ribonucleoprotein domains), a less well conserved linker region, and a proline-rich C-terminal conserved domain (CTD). PABP-3 is a testis-specific poly(A)-binding protein specifically expressed in round spermatids. It is mainly found in mammalian and may play an important role in the testis-specific regulation of mRNA homeostasis. PABP-3 shows significant sequence similarity to PABP-1. However, it binds to poly(A) with a lower affinity than PABP-1. Moreover, PABP-1 possesses an A-rich sequence in its 5'-UTR and allows binding of PABP and blockage of translation of its own mRNA. In contrast, PABP-3 lacks the A-rich sequence in its 5'-UTR. PABP-4 is an inducible poly(A)-binding protein (iPABP) that is primarily localized to the cytoplasm. It shows significant sequence similarity to PABP-1 as well. The RNA binding properties of PABP-1 and PABP-4 appear to be identical. PABP-5 is encoded by PABPC5 gene within the X-specific subinterval, and expressed in fetal brain and in a range of adult tissues in mammals, such as ovary and testis. It may play an important role in germ cell development. Moreover, unlike other PABPs, PABP-5 contains only four RRMs, but lacks both the linker region and the CTD. PABP-1-like and PABP-1-like 2 are the orthologs of PABP-1. PABP-4-like is the ortholog of PABP-5. Their cellular functions remain unclear. The family also includes yeast PABP, a conserved poly(A) binding protein containing poly(A) tails that can be attached to the 3'-ends of mRNAs. The yeast PABP and its homologs may play important roles in the initiation of translation and in mRNA decay. Like vertebrate PABP-1, the yeast PABP contains four RRMs, a linker region, and a proline-rich CTD as well. The first two RRMs are mainly responsible for specific binding to poly(A). The proline-rich region may be involved in protein-protein interactions.

                          10        20        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 2071133334 157 LYLGNLNPKMTEQQLCEVFGRFGPLASVKIMwprSDEERARGRNCGFVAFMNRKDGERAMKNLNGKDVMSFEMKLGW 233
Cdd:cd12378     2 LYVGDLHPDVTEAMLYEKFSPAGPVLSIRVC---RDAVTRRSLGYAYVNFQQPADAERALDTLNFDVIKGKPIRIMW 75

RNA recognition motif 2 (RRM2) found in RNA-binding protein MRN1 and similar proteins; This subgroup corresponds to the RRM2 of MRN1, also termed multicopy suppressor of RSC-NHP6 synthetic lethality protein 1, or post-transcriptional regulator of 69 kDa, which is a RNA-binding protein found in yeast. Although its specific biological role remains unclear, MRN1 might be involved in translational regulation. Members in this family contain four copies of conserved RNA recognition motif (RRM), also known as RBD (RNA binding domain) or RNP (ribonucleoprotein domain).

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 2071133334 153 STTNLYLGNLNPKMTEQQLCEVFGRFGPLASVKIMwprsdeeraRGRNCGFVAFMNRKDGERAMKNL 219
Cdd:cd12523     2 ASRNVYLGNLPESITEEELREDLEKFGPIDQIKIV---------KEKNIAFVHFLSIANAIKVVTTL 59

RNA recognition motif 2 (RRM2) found in putative RNA binding motif protein 15B (RBM15B) from vertebrate; This subgroup corresponds to the RRM2 of RBM15B, also termed one twenty-two 3 (OTT3), a paralog of RNA binding motif protein 15 (RBM15), also known as One-twenty two protein 1 (OTT1). Like RBM15, RBM15B has post-transcriptional regulatory activity. It is a nuclear protein sharing with RBM15 the association with the splicing factor compartment and the nuclear envelope as well as the binding to mRNA export factors NXF1 and Aly/REF. RBM15B belongs to the Spen (split end) protein family, which shares a domain architecture comprising of three N-terminal RNA recognition motifs (RRMs), also known as RBD (RNA binding domain) or RNP (ribonucleoprotein domain), and a C-terminal SPOC (Spen paralog and ortholog C-terminal) domain.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2071133334 153 STTNLYLGNLNPKMTEQQLCEVFGRFGPLASVKIMWPrsdeERARGRNCGFVAFMNRKDGERAMKNLNGKDVMSFEMKLG 232
Cdd:cd12556     7 ATRNLFIGNLDHNVSEVELRRAFEKYGIIEEVVIKRP----ARGQGGAYAFLKFQNLDMAHRAKVAMSGRVIGRNPIKIG 82

                  ...
gi 2071133334 233 WGK 235
Cdd:cd12556    83 YGK 85

RNA recognition motif 2 (RRM2) found in the Hu proteins family; This subfamily corresponds to the RRM2 of Hu proteins family which represents a group of RNA-binding proteins involved in diverse biological processes. Since the Hu proteins share high homology with the Drosophila embryonic lethal abnormal vision (ELAV) protein, the Hu family is sometimes referred to as the ELAV family. Drosophila ELAV is exclusively expressed in neurons and is required for the correct differentiation and survival of neurons in flies. The neuronal members of the Hu family include Hu-antigen B (HuB or ELAV-2 or Hel-N1), Hu-antigen C (HuC or ELAV-3 or PLE21), and Hu-antigen D (HuD or ELAV-4), which play important roles in neuronal differentiation, plasticity and memory. HuB is also expressed in gonads. Hu-antigen R (HuR or ELAV-1 or HuA) is the ubiquitously expressed Hu family member. It has a variety of biological functions mostly related to the regulation of cellular response to DNA damage and other types of stress. Moreover, HuR has an anti-apoptotic function during early cell stress response. It binds to mRNAs and enhances the expression of several anti-apoptotic proteins, such as p21waf1, p53, and prothymosin alpha. HuR also has pro-apoptotic function by promoting apoptosis when cell death is unavoidable. Furthermore, HuR may be important in muscle differentiation, adipogenesis, suppression of inflammatory response and modulation of gene expression in response to chronic ethanol exposure and amino acid starvation. Hu proteins perform their cytoplasmic and nuclear molecular functions by coordinately regulating functionally related mRNAs. In the cytoplasm, Hu proteins recognize and bind to AU-rich RNA elements (AREs) in the 3' untranslated regions (UTRs) of certain target mRNAs, such as GAP-43, vascular epithelial growth factor (VEGF), the glucose transporter GLUT1, eotaxin and c-fos, and stabilize those ARE-containing mRNAs. They also bind and regulate the translation of some target mRNAs, such as neurofilament M, GLUT1, and p27. In the nucleus, Hu proteins function as regulators of polyadenylation and alternative splicing. Each Hu protein contains three RNA recognition motifs (RRMs), also termed RBDs (RNA binding domains) or RNPs (ribonucleoprotein domains). RRM1 and RRM2 may cooperate in binding to an ARE. RRM3 may help to maintain the stability of the RNA-protein complex, and might also bind to poly(A) tails or be involved in protein-protein interactions.

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 2071133334 156 NLYLGNLNPKMTEQQLCEVFGRFGPLASVKIMwprSDEERARGRNCGFVAFMNRKDGERAMKNLNGK 222
Cdd:cd12652     2 NLYVSGLPKTMTQKELEQLFSQFGRIITSRIL---CDNVTGLSRGVGFIRFDKRVEAERAIKALNGT 65

RNA recognition motif 1 (RRM1) found in the Hu proteins family, Drosophila sex-lethal (SXL), and similar proteins; This subfamily corresponds to the RRM1 of Hu proteins and SXL. The Hu proteins family represents a group of RNA-binding proteins involved in diverse biological processes. Since the Hu proteins share high homology with the Drosophila embryonic lethal abnormal vision (ELAV) protein, the Hu family is sometimes referred to as the ELAV family. Drosophila ELAV is exclusively expressed in neurons and is required for the correct differentiation and survival of neurons in flies. The neuronal members of the Hu family include Hu-antigen B (HuB or ELAV-2 or Hel-N1), Hu-antigen C (HuC or ELAV-3 or PLE21), and Hu-antigen D (HuD or ELAV-4), which play important roles in neuronal differentiation, plasticity and memory. HuB is also expressed in gonads. Hu-antigen R (HuR or ELAV-1 or HuA) is ubiquitously expressed Hu family member. It has a variety of biological functions mostly related to the regulation of cellular response to DNA damage and other types of stress. Hu proteins perform their cytoplasmic and nuclear molecular functions by coordinately regulating functionally related mRNAs. In the cytoplasm, Hu proteins recognize and bind to AU-rich RNA elements (AREs) in the 3' untranslated regions (UTRs) of certain target mRNAs, such as GAP-43, vascular epithelial growth factor (VEGF), the glucose transporter GLUT1, eotaxin and c-fos, and stabilize those ARE-containing mRNAs. They also bind and regulate the translation of some target mRNAs, such as neurofilament M, GLUT1, and p27. In the nucleus, Hu proteins function as regulators of polyadenylation and alternative splicing. Each Hu protein contains three RNA recognition motifs (RRMs), also termed RBDs (RNA binding domains) or RNPs (ribonucleoprotein domains). RRM1 and RRM2 may cooperate in binding to an ARE. RRM3 may help to maintain the stability of the RNA-protein complex, and might also bind to poly(A) tails or be involved in protein-protein interactions. This family also includes the sex-lethal protein (SXL) from Drosophila melanogaster. SXL governs sexual differentiation and X chromosome dosage compensation in flies. It induces female-specific alternative splicing of the transformer (tra) pre-mRNA by binding to the tra uridine-rich polypyrimidine tract at the non-sex-specific 3' splice site during the sex-determination process. SXL binds to its own pre-mRNA and promotes female-specific alternative splicing. It contains an N-terminal Gly/Asn-rich domain that may be responsible for the protein-protein interaction, and tandem RRMs that show high preference to bind single-stranded, uridine-rich target RNA transcripts.

                          10        20        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|.
gi 2071133334 156 NLYLGNLNPKMTEQQLCEVFGRFGPLASVKIMwprsdEERARGRNC--GFVAFMNRKDGERAMKNLNGKDV 224
Cdd:cd12375     1 NLIVNYLPQSMTQEELRSLFGAIGPIESCKLV-----RDKITGQSLgyGFVNYRDPNDARKAINTLNGLDL 66

RNA recognition motif (RRM) found in cleavage stimulation factor subunit 2 (CSTF2), yeast ortholog mRNA 3'-end-processing protein RNA15 and similar proteins; This subfamily corresponds to the RRM domain of CSTF2, its tau variant and eukaryotic homologs. CSTF2, also termed cleavage stimulation factor 64 kDa subunit (CstF64), is the vertebrate conterpart of yeast mRNA 3'-end-processing protein RNA15. It is expressed in all somatic tissues and is one of three cleavage stimulatory factor (CstF) subunits required for polyadenylation. CstF64 contains an N-terminal RNA recognition motif (RRM), also known as RBD (RNA binding domain) or RNP (ribonucleoprotein domain), a CstF77-binding domain, a repeated MEARA helical region and a conserved C-terminal domain reported to bind the transcription factor PC-4. During polyadenylation, CstF interacts with the pre-mRNA through the RRM of CstF64 at U- or GU-rich sequences within 10 to 30 nucleotides downstream of the cleavage site. CSTF2T, also termed tauCstF64, is a paralog of the X-linked cleavage stimulation factor CstF64 protein that supports polyadenylation in most somatic cells. It is expressed during meiosis and subsequent haploid differentiation in a more limited set of tissues and cell types, largely in meiotic and postmeiotic male germ cells, and to a lesser extent in brain. The loss of CSTF2T will cause male infertility, as it is necessary for spermatogenesis and fertilization. Moreover, CSTF2T is required for expression of genes involved in morphological differentiation of spermatids, as well as for genes having products that function during interaction of motile spermatozoa with eggs. It promotes germ cell-specific patterns of polyadenylation by using its RRM to bind to different sequence elements downstream of polyadenylation sites than does CstF64. The family also includes yeast ortholog mRNA 3'-end-processing protein RNA15 and similar proteins. RNA15 is a core subunit of cleavage factor IA (CFIA), an essential transcriptional 3'-end processing factor from Saccharomyces cerevisiae. RNA recognition by CFIA is mediated by an N-terminal RRM, which is contained in the RNA15 subunit of the complex. The RRM of RNA15 has a strong preference for GU-rich RNAs, mediated by a binding pocket that is entirely conserved in both yeast and vertebrate RNA15 orthologs.

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 2071133334 157 LYLGNLNPKMTEQQLCEVFGRFGPLASVKIMWprsDEERARGRNCGFVAFMNRKDGERAMKNLNGKDVM 225
Cdd:cd12398     3 VFVGNIPYDATEEQLKEIFSEVGPVVSFRLVT---DRETGKPKGYGFCEFRDAETALSAVRNLNGYELN 68

RNA recognition motif 1 (RRM1) found in vertebrate Hu-antigen B (HuB); This subgroup corresponds to the RRM1 of HuB, also termed ELAV-like protein 2 (ELAV-2), or ELAV-like neuronal protein 1, or nervous system-specific RNA-binding protein Hel-N1 (Hel-N1), one of the neuronal members of the Hu family. The neuronal Hu proteins play important roles in neuronal differentiation, plasticity and memory. HuB is also expressed in gonads and is up-regulated during neuronal differentiation of embryonic carcinoma P19 cells. Like other Hu proteins, HuB contains three RNA recognition motifs (RRMs), also termed RBDs (RNA binding domains) or RNPs (ribonucleoprotein domains). RRM1 and RRM2 may cooperate in binding to an AU-rich RNA element (ARE). RRM3 may help to maintain the stability of the RNA-protein complex, and might also bind to poly(A) tails or be involved in protein-protein interactions.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2071133334 151 DPSTTNLYLGNLNPKMTEQQLCEVFGRFGPLASVKIMwprSDEERARGRNCGFVAFMNRKDGERAMKNLNGKDVMSFEMK 230
Cdd:cd12771     1 EDSKTNLIVNYLPQNMTQEELKSLFGSIGEIESCKLV---RDKITGQSLGYGFVNYIEPKDAEKAINTLNGLRLQTKTIK 77

                  ....*
gi 2071133334 231 LGWGK 235
Cdd:cd12771    78 VSYAR 82