RING finger (Really Interesting New Gene) domain and U-box domain superfamily; The RING finger is a specialized type of Zn-finger of 40 to 60 residues that binds two atoms of zinc. It is defined by the "cross-brace" motif that chelates zinc atoms by eight amino acid residues, typically Cys or His, arranged in a characteristic spacing. Canonical RING motifs have been categorized into two major subclasses, RING-HC (C3HC4-type) and RING-H2 (C3H2C3-type), according to their Cys/His content. There are also many variants of RING fingers: some have different Cys/His patterns while some lack a single Cys or His residue at typical Zn ligand positions (the fourth or eighth zinc ligand is prevalently exchanged for an Asp, which can indeed chelate Zn in a RING finger as well). C4C4-, C3HC3D-, C2H2C4-, and C3HC5-type RING fingers are closely related to RING-HC fingers. In contrast, C4HC3- (RING-CH alias RINGv), C3H3C2-, C3H2C2D-, C3DHC3-, and C4HC2H-type RING fingers are more closely related to RING-H2 fingers. However, not all RING finger-containing proteins display regular RING finger features, and the RING finger family has turned out to be multifarious. The degenerate RING fingers of the Siz/PIAS RING (SP-RING) family proteins and sporulation protein RMD5, are characterized by lacking the second, fifth, and sixth Zn2+ ion-coordinating residues. They bind only one Zn2+ ion. On the other hand, the RING fingers of the human APC11 and RBX1 proteins can bind a third Zn atom since they harbor four additional Zn ligands. U-box is a modified form of the RING finger domain that lacks metal chelating Cys and His residues. It resembles the cross-brace RING structure consisting of three beta-sheets and a single alpha-helix, which would be stabilized by salt bridges instead of chelated metal ions. U-box proteins are widely distributed among eukaryotic organisms and show a higher prevalence in plants than in other organisms. RING finger/U-box-containing proteins are a group of diverse proteins with a variety of cellular functions, including oncogenesis, development, viral replication, signal transduction, the cell cycle and apoptosis. Many of them are ubiquitin-protein ligases (E3s) that serve as scaffolds for binding to ubiquitin-conjugating enzymes (E2s, also referred to as ubiquitin carrier proteins or UBCs) in close proximity to substrate proteins, which enable efficient transfer of ubiquitin from E2 to the substrates.

                           10        20
                   ....*....|....*....|..
gi 1910397938 1207 CRACINQHLMNNKDCFFCKATI 1228
Cdd:cd16541     23 CRSCINRHLMNNKECFFCKATI 44

SPRY domain; SPRY Domain is named from SPla and the RYanodine Receptor and it is found in many eukaryotic proteins with a wide range of functions. It is a protein-interaction module involved in many important signalling pathways like RNA processing, regulation of histone H3 methylation, innate immunity or embryonic development. It can be divided into 11 subfamilies based on amino acid sequence similarity or the presence of additional protein domains. The greater SPRY family is divided into the SPRY/B30.2 (which contains a PRY extension at the N-terminal) and SPRY-only sub-families which are preceded by a subdomain that is structurally similar to the PRY region. SPRY/B30.2 structures revealed a bent beta-sandwich fold comprised of two beta-sheets. Distant homologs are domains in butyrophilin/ marenostrin/pyrin.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1910397938    1 MQIGWCTINCRFNQEEGVGDTHNSYAYDGNRVRK-WNVTTTNYGKA-WAAGDIVSCLIDLDDGTLSFSLNGVSLGTAFED 78
Cdd:pfam00622   16 WRVGWATKSVPRKGERFLGDESGSWGYDGWTGKKyWASTSPLTGLPlFEPGDVIGCFLDYEAGTISFTKNGKSLGYAFRD 95

                           90       100
                   ....*....|....*....|....*...
gi 1910397938   79 LsRGPGMaYFPAISLSFKESVAFNFGSR 106
Cdd:pfam00622   96 V-PFAGP-LFPAVSLGAGEGLKFNFGLR 121

RING finger, HC subclass, found in RING finger protein 123 (RNF123) and similar proteins; RNF123, also known as Kip1 ubiquitination-promoting complex protein 1 (KPC1), is an E3 ubiquitin-protein ligase that mediates ubiquitination and proteasomal processing of the nuclear factor-kappaB 1 (NF-kappaB1) precursor p105 to the p50 active subunit that restricts tumor growth. It also regulates degradation of heterochromatin protein 1alpha (HP1alpha) and 1beta (HP1beta) in lamin A/C knock-down cells. Moreover, RNF123, together with Kip1 ubiquitylation-promoting complex 2 (KPC2), forms the Kip1 ubiquitination-promoting complex (KPC), acting as a cytoplasmic ubiquitin ligase that regulates degradation of the cyclin-dependent kinase inhibitor p27 (Kip1) at the G1 phase of the cell cycle. RNF123 may also function as a clinically relevant, peripheral state marker of depression. RNF123 contains a C3HC4-type RING-HC finger at the C-terminus.

                           10        20
                   ....*....|....*....|..
gi 1910397938 1207 CRACINQHLMNNKDCFFCKATI 1228
Cdd:cd16541     23 CRSCINRHLMNNKECFFCKATI 44

SPRY domain; SPRY domains, first identified in the SP1A kinase of Dictyostelium and rabbit Ryanodine receptor (hence the name), are homologous to B30.2. SPRY domains have been identified in at least 11 protein families, covering a wide range of functions, including regulation of cytokine signaling (SOCS), RNA metabolism (DDX1 and hnRNP), immunity to retroviruses (TRIM5alpha), intracellular calcium release (ryanodine receptors or RyR) and regulatory and developmental processes (HERC1 and Ash2L). B30.2 also contains residues in the N-terminus that form a distinct PRY domain structure; i.e. B30.2 domain consists of PRY and SPRY subdomains. B30.2 domains comprise the C-terminus of three protein families: BTNs (receptor glycoproteins of immunoglobulin superfamily); several TRIM proteins (composed of RING/B-box/coiled-coil or RBCC core); Stonutoxin (secreted poisonous protein of the stonefish Synanceia horrida). TRIM/RBCC proteins are involved in a variety of processes, including apoptosis, cell cycle regulation, cell growth, senescence, viral response, meiosis, cell differentiation, and vesicular transport. Genes belonging to this family are implicated in several human diseases that vary from cancer to rare genetic syndromes. The PRY-SPRY domain in these TRIM families is suggested to serve as the target binding site. While SPRY domains are evolutionarily ancient, B30.2 domains are a more recent adaptation where the SPRY/PRY combination is a possible component of immune defense. Mutations found in the SPRY-containing proteins have shown to cause Mediterranean fever and Opitz syndrome.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1910397938    1 MQIGWCTINCRFNQEEGVGDTHNSYAYDGNRVRKWNVTT-TNYGKAWAAGDIVSCLIDLDDGTLSFSLNGVSLGTAFEDL 79
Cdd:cd11709     17 IQVGWATKSFSLDGEGGVGDDEESWGYDGSRLRKGHGGSsGPGGRPWKSGDVVGCLLDLDEGTLSFSLNGKDLGVAFTNL 96

                           90       100
                   ....*....|....*....|...
gi 1910397938   80 SRGPGmAYFPAISLSFKESVAFN 102
Cdd:cd11709     97 FLKGG-GLYPAVSLGSGQGVTIN 118

SPRY domain; SPRY Domain is named from SPla and the RYanodine Receptor and it is found in many eukaryotic proteins with a wide range of functions. It is a protein-interaction module involved in many important signalling pathways like RNA processing, regulation of histone H3 methylation, innate immunity or embryonic development. It can be divided into 11 subfamilies based on amino acid sequence similarity or the presence of additional protein domains. The greater SPRY family is divided into the SPRY/B30.2 (which contains a PRY extension at the N-terminal) and SPRY-only sub-families which are preceded by a subdomain that is structurally similar to the PRY region. SPRY/B30.2 structures revealed a bent beta-sandwich fold comprised of two beta-sheets. Distant homologs are domains in butyrophilin/ marenostrin/pyrin.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1910397938    1 MQIGWCTINCRFNQEEGVGDTHNSYAYDGNRVRK-WNVTTTNYGKA-WAAGDIVSCLIDLDDGTLSFSLNGVSLGTAFED 78
Cdd:pfam00622   16 WRVGWATKSVPRKGERFLGDESGSWGYDGWTGKKyWASTSPLTGLPlFEPGDVIGCFLDYEAGTISFTKNGKSLGYAFRD 95

                           90       100
                   ....*....|....*....|....*...
gi 1910397938   79 LsRGPGMaYFPAISLSFKESVAFNFGSR 106
Cdd:pfam00622   96 V-PFAGP-LFPAVSLGAGEGLKFNFGLR 121

SPRY domain associated with DEAD box gene DDX1; This SPRY domain is associated with the DEAD box gene, DDX1, an RNA-dependent ATPase involved in HIV-1 Rev function and virus replication. It is suggested that DDX1 acts as a cellular cofactor by promoting oligomerization of Rev on the Rev response element (RRE). DDX1 RNA is overexpressed in breast cancer, data showing a strong and independent association between poor prognosis and deregulation of the DEAD box protein DDX1, thus potentially serving as an effective prognostic biomarker for early recurrence in primary breast cancer. DDX1 also interacts with RelA and enhances nuclear factor kappaB-mediated transcription. DEAD-box proteins are associated with all levels of RNA metabolism and function, and have been implicated in translation initiation, transcription, RNA splicing, ribosome assembly, RNA transport, and RNA decay.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1910397938    3 IGWCTINCRFNqeegVGDTHNSYAYDGNRVRKWNVTTTNYGKAWAAGDIVSCLIDLDDGTLSFSLNGVSLGTAFEDLSRG 82
Cdd:cd12873     56 VGWSTEDASLD----LGTDKFGFGYGGTGKKSHGRQFDDYGEPFGLGDVIGCYLDLDNGTISFSKNGKDLGKAFDIPPHL 131

                           90       100
                   ....*....|....*....|....*
gi 1910397938   83 PGMAYFPAISLSFKEsVAFNFGSRP 107
Cdd:cd12873    132 RNSALFPAVCLKNAE-VEFNFGDKP 155

SPRY domain in Ran binding proteins, SSH4, HECT E3 and SPRYD3; This family includes SPRY domains found in Ran binding proteins (RBP or RanBPM) 9 and 10, SSH4 (suppressor of SHR3 null mutation protein 4), SPRY domain-containing protein 3 (SPRYD3) as well as HECT, a C-terminal catalytic domain of a subclass of ubiquitin-protein ligase (E3). RanBP9 and RanBP10 act as androgen receptor (AR) coactivators. Both consist of the N-terminal proline- and glutamine-rich regions, the SPRY domain, and LisH-CTLH and CRA motifs. The SPRY domain in SSH4 may be involved in cargo recognition, either directly or by combination with other adaptors, possibly leading to a higher selectivity. SPRYD3 is highly expressed in most tissues in humans, possibly involved in important cellular processes. HECT E3 mediates the direct transfer of ubiquitin from E2 to substrate.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1910397938    3 IGWCTINCRFNQeeGVGDTHNSYAYDGN--RVRKWNVTTTNYGKAWAAGDIVSCLIDLDDGTLSFSLNGVSLGTAFEDLS 80
Cdd:cd12885     33 IGFCTSGFPLNR--MPGWEDGSYGYHGDdgRVYLGGGEGENYGPPFGTGDVVGCGINFKTGEVFFTKNGELLGTAFENVV 110

                           90       100
                   ....*....|....*....|....*
gi 1910397938   81 RGPgmaYFPAISLSFK-ESVAFNFG 104
Cdd:cd12885    111 KGR---LYPTVGLGSPgVKVRVNFG 132

SPRY domain in Ash2; This SPRY domain is found at the C-terminus of Ash2 (absent, small, or homeotic discs 2) -like proteins, core components of all mixed-lineage leukemia (MLL) family histone methyltransferases. Ash2 is a member of the trithorax group of transcriptional regulators of the Hox genes. Recent studies show that the SPRY domain of Ash2 mediates the interaction with RbBP5 and has an important role in regulating the methyltransferase activity of MLL complexes. In yeast, Ash2 is involved in histone methylation and is required for the earliest stages of embryogenesis.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1910397938    3 IGWCTINCRFnqEEGVG-DTHnSYAY---DGNRVRKWNVTTtNYGKAWAAGDIVSCLIDLddGTLSFSLNGVSLGTAFED 78
Cdd:cd12872     49 VGWSRREASL--QAPVGyDKY-SYAIrdkDGSKFHQSRGKP-YGEPGFKEGDVIGFLITL--PKIEFFKNGKSQGVAFED 122

                           90       100
                   ....*....|....*....|....*.
gi 1910397938   79 LSrGPGmAYFPAISLSFKESVAFNFG 104
Cdd:cd12872    123 IY-GTG-GYYPAVSLYKGATVTINFG 146

SPRY domain 1 (SPRY1) of ryanodine receptor (RyR); This SPRY domain is the first of three structural repeats in all three isoforms of the ryanodine receptor (RyR), which are the major Ca2+ release channels in the membranes of sarcoplasmic reticulum (SR). There are three RyR genes in mammals; the skeletal RyR1, the cardiac RyR2 and the brain RyR3. The three SPRY domains are located in the N-terminal part of the cytoplasmic region of the RyRs, but no specific function has been found for this first SPRY domain of the RyRs.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1910397938   17 GVGDTHNSYAYDGNRV---RKWNVTTTNYGKAWAAGDIVSCLIDLDDGTLSFSLNGVSLGTAFEDLSRgPGMaYFPAISL 93
Cdd:cd12877     63 GVGDDLYSYGFDGLHLwtgGRSRRVTSGTQHLLKKGDVVGCCLDLSVPSISFRVNGRPVQGMFENFNL-DGM-FFPVMSF 140

                           90
                   ....*....|.
gi 1910397938   94 SFKESVAFNFG 104
Cdd:cd12877    141 SAGVSCRFLLG 151

SPRY domain-like in bacteria; This family contains SPRY-like domains that are found only in bacterial and are mostly uncharacterized. SPRY domains, first identified in the SP1A kinase of Dictyostelium and rabbit Ryanodine receptor (hence the name), are homologous to B30.2. SPRY domains have been identified in at least 11 eukaryotic protein families, covering a wide range of functions, including regulation of cytokine signaling (SOCS), RNA metabolism (DDX1 and hnRNP), immunity to retroviruses (TRIM5alpha), intracellular calcium release (ryanodine receptors or RyR) and regulatory and developmental processes (HERC1 and Ash2L).

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1910397938   12 FNQEEGVGDTHNSYAYDGNRVRKWNVTTTnYGKAWAAGDIVSCLIDLDDGTLSFSLNGVSLGT---AFEDLSRGPGMAYF 88
Cdd:cd12886     33 LNGIELSSIGYSLGVYSGNKLSNGSSVAT-YGAGFTAGDVIGVALDLDAGKIWFYKNGVWQGGgdpAPGTNPAFAGTAMY 111

                           90
                   ....*....|....*...
gi 1910397938   89 PAISL--SFKESVAFNFG 104
Cdd:cd12886    112 PAVTGgsSTGGSFTANFG 129

SPRY domain 3 (SPRY3) of ryanodine receptor (RyR); This SPRY domain (SPRY3) is the third of three structural repeats in all three isoforms of the ryanodine receptor (RyR), which are the major Ca2+ release channels in the membranes of sarcoplasmic reticulum (SR). There are three RyR genes in mammals; the skeletal RyR1, the cardiac RyR2 and the brain RyR3. The three SPRY domains are located in the N-terminal part of the cytoplasmic region of the RyRs, but no specific function has been found for this third SPRY domain of the RyRs.

                           10        20        30        40        50        60        70
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|...
gi 1910397938   36 NVTTTNYGKAWAAGDIVSCLIDLDDGTLSFSLNGVSLGTAF--EdlsrgPGMAYFPAISL--SFKESVAFNFG 104
Cdd:cd12879     84 AEVGQDSSGRASQGLLIGCLIDTATGLLTFTANGKETSTRFqvE-----PGTKLFPAVFVrpTSKEVLQFELG 151

SPRY domain in the suppressor of cytokine signaling 1, 2, 4 families (SOCS1, SOCS2, SOCS4); The SPRY domain-containing SOCS box protein family (SPSB1-4, also known as SSB-1 to -4) is composed of a central SPRY protein interaction domain and a C-terminal SOCS box. All four SPSB proteins interact with c-Met, the hepatocyte growth factor receptor, but only SPSB1, SPSB2, and SPSB4 interact with prostate apoptosis response protein 4 (Par-4). They are negative regulators that recruit the ECS E3 ubiquitin ligase complex to polyubiquitinate inducible nitric-oxide synthase (iNOS), resulting in its proteasomal degradation, thus contributing to protection against the cytotoxic effect of iNOS in activated macrophages. It has been shown that SPSB1 and SPSB4 induce the degradation of iNOS more strongly than SPSB2. The Drosophila melanogaster SPSB1 homolog, GUSTAVUS, interacts with the DEAD box RNA helicase Vasa. Suppressor of cytokine signaling (SOCS) proteins negatively regulate signaling from JAK-associated cytokine receptor complexes, and play key roles in the regulation of immune homeostasis.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1910397938    3 IGWCTINCRFnQEEG----VGDTHNSYAYDGNRVR-------KWNVTTTNY---GKAWAAGDIVSCLIDLDDGTLSFSLN 68
Cdd:cd12906     62 VGVATKDAPL-HCVGytslVGSNEESWGWDIGRNKlyhdsknQPGWTYPAFlepDENFVVPDKFLVVLDMDEGTLSFVVD 140

                           90       100
                   ....*....|....*....|....
gi 1910397938   69 GVSLGTAFEDLSrgpGMAYFPAIS 92
Cdd:cd12906    141 GQYLGVAFRGLK---GKKLYPIVS 161

SPRY domain in Fbxo45 and suppressors of cytokine signaling (SOCS) proteins; This family consists of the SPRY domain-containing SOCS box protein family (SPSB1-4, also known as SSB-1 to -4) as well as F-box protein 45 (Fbxo45), a novel synaptic E3 and ubiquitin ligase. The SPSB protein is composed of a central SPRY protein interaction domain and a C-terminal SOCS box. SPSB1, SPSB2, and SPSB4 interact with prostate apoptosis response protein 4 (Par-4) and are negative regulators that recruit the ECS E3 ubiquitin ligase complex to polyubiquitinate inducible nitric-oxide synthase (iNOS), resulting in its proteasomal degradation. Fbxo45 is related to this family; it is located N-terminal to the SPRY domain, and known to induce the degradation of a synaptic vesicle-priming factor, Munc13-1, via the SPRY domain, thus playing an important role in the regulation of neurotransmission by modulating Munc13-1 at the synapse. Suppressor of cytokine signaling (SOCS) proteins negatively regulate signaling from JAK-associated cytokine receptor complexes, and play key roles in the regulation of immune homeostasis.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1910397938   18 VGDTHNSYAYD---GNRVRKWNVTTTNY---GKAWAAGDIVSCLIDLDDGTLSFSLNGVSLGTAFEDLsrgPGMAYFPAI 91
Cdd:cd12875     79 LGSNSESWGWDlgdNKLYHNGKKVIGSYpakSENYQVPDRILVILDMEDGTLAFEANGEYLGVAFRGL---PGKLLYPAV 155

                   .
gi 1910397938   92 S 92
Cdd:cd12875    156 S 156