origin recognition complex 1 protein; Provisional

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 15235420   424 EKAKATLLLATRPKSLPCRSKEMEEITSFIKGSISDDQClGRCMYIHGVPGTGKTISVLSVMKNLKAEVEEGSVSPYCFV 503
Cdd:PTZ00112  742 DKAIRMMQLDVVPKYLPCREKEIKEVHGFLESGIKQSGS-NQILYISGMPGTGKTATVYSVIQLLQHKTKQKLLPSFNVF 820

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 15235420   504 EINGLKLASPENIYSVIYEALSGhrvgwKKALQCLNErFAEGKRIGKEDEKPCILLI----DELDLLVTRNQSVLYNILD 579
Cdd:PTZ00112  821 EINGMNVVHPNAAYQVLYKQLFN-----KKPPNALNS-FKILDRLFNQNKKDNRNVSiliiDEIDYLITKTQKVLFTLFD 894

                         170       180       190       200       210       220       230       240
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 15235420   580 WPTKPNSKLVVLGIANTMDLPEKLLPRISSRMGIQRLCFGPYNHTQLQEIISTRL-NGIDAFEKTAIEFASRKVAAISGD 658
Cdd:PTZ00112  895 WPTKINSKLVLIAISNTMDLPERLIPRCRSRLAFGRLVFSPYKGDEIEKIIKERLeNCKEIIDHTAIQLCARKVANVSGD 974

                         250       260       270       280       290       300
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 15235420   659 ARRALEICRRAAEvadhrlntNKsaKNQLVIMADVEAAIQEMFQAPHIQVMKSVSKLSKIFLTAMVHEL 727
Cdd:PTZ00112  975 IRKALQICRKAFE--------NK--RGQKIVPRDITEATNQLFDSPLTNAINYLPWPFKMFLTCLIVEL 1033

origin recognition complex 1 protein; Provisional

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 15235420   424 EKAKATLLLATRPKSLPCRSKEMEEITSFIKGSISDDQClGRCMYIHGVPGTGKTISVLSVMKNLKAEVEEGSVSPYCFV 503
Cdd:PTZ00112  742 DKAIRMMQLDVVPKYLPCREKEIKEVHGFLESGIKQSGS-NQILYISGMPGTGKTATVYSVIQLLQHKTKQKLLPSFNVF 820

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 15235420   504 EINGLKLASPENIYSVIYEALSGhrvgwKKALQCLNErFAEGKRIGKEDEKPCILLI----DELDLLVTRNQSVLYNILD 579
Cdd:PTZ00112  821 EINGMNVVHPNAAYQVLYKQLFN-----KKPPNALNS-FKILDRLFNQNKKDNRNVSiliiDEIDYLITKTQKVLFTLFD 894

                         170       180       190       200       210       220       230       240
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 15235420   580 WPTKPNSKLVVLGIANTMDLPEKLLPRISSRMGIQRLCFGPYNHTQLQEIISTRL-NGIDAFEKTAIEFASRKVAAISGD 658
Cdd:PTZ00112  895 WPTKINSKLVLIAISNTMDLPERLIPRCRSRLAFGRLVFSPYKGDEIEKIIKERLeNCKEIIDHTAIQLCARKVANVSGD 974

                         250       260       270       280       290       300
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 15235420   659 ARRALEICRRAAEvadhrlntNKsaKNQLVIMADVEAAIQEMFQAPHIQVMKSVSKLSKIFLTAMVHEL 727
Cdd:PTZ00112  975 IRKALQICRKAFE--------NK--RGQKIVPRDITEATNQLFDSPLTNAINYLPWPFKMFLTCLIVEL 1033

orc1/cdc6 family replication initiation protein; Members of this protein family are found exclusively in the archaea. This set of DNA binding proteins shows homology to the origin recognition complex subunit 1/cell division control protein 6 family in eukaryotes. Several members may be found in genome and interact with each other. [DNA metabolism, DNA replication, recombination, and repair]

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 15235420   427 KATLLLATRPKSLPCRSKEMEEITSFIK----GSISDDqclgrcMYIHGVPGTGKTISVLSVMKNLKAEVEEGSVsPYCF 502
Cdd:TIGR02928   5 RDLLEPDYVPDRIVHRDEQIEELAKALRpilrGSRPSN------VFIYGKTGTGKTAVTKYVMKELEEAAEDRDV-RVVT 77

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 15235420   503 VEINGLKLASPENIYSVIYEALSGHRV-----GW------KKALQCLNERFA-------EGKRIGKEDEkpcillideld 564
Cdd:TIGR02928  78 VYVNCQILDTLYQVLVELANQLRGSGEevpttGLstsevfRRLYKELNERGDsliivldEIDYLVGDDD----------- 146

                         170       180       190       200       210       220       230       240
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 15235420   565 llvtrnqSVLYNILDWPTK---PNSKLVVLGIANTMDLPEKLLPRISSRMGIQRLCFGPYNHTQLQEIISTRLNGI---D 638
Cdd:TIGR02928 147 -------DLLYQLSRARSNgdlDNAKVGVIGISNDLKFRENLDPRVKSSLCEEEIIFPPYDAEELRDILENRAEKAfydG 219

                         250       260       270       280       290       300       310       320
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 15235420   639 AFEKTAIEFASRKVAAISGDARRALEICRRAAEVADHRlntnksaKNQLVIMADVEAAiQEmfQAPHIQVMKSVSKL--- 715
Cdd:TIGR02928 220 VLDDGVIPLCAALAAQEHGDARKAIDLLRVAGEIAERE-------GAERVTEDHVEKA-QE--KIEKDRLLELIRGLpth 289

                  ....*...
gi 15235420   716 SKIFLTAM 723
Cdd:TIGR02928 290 SKLVLLAI 297

BAH domain; This domain has been called BAH (Bromo adjacent homology) domain and has also been called ELM1 and BAM (Bromo adjacent motif) domain. The function of this domain is unknown but may be involved in protein-protein interaction.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 15235420   250 ARIDKLWKEVDDGVYWIRARWYMIPEETVSGRQPHNLKRELYLTNDFADIEMECILRHCSVKCPKEFSKASNDG---DDV 326
Cdd:pfam01426  23 ARIEELFEDTKNGKKMVRVQWFYRPEETVHRAGKAFNKDELFLSDEEDDVPLSAIIGKCSVLHKSDLESLDPYKikePDD 102

                          90
                  ....*....|....*..
gi 15235420   327 FLCEYEYDVHWRSFKRL 343
Cdd:pfam01426 103 FFCELLYDPKTKSFKKL 119

origin recognition complex 1 protein; Provisional

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 15235420   424 EKAKATLLLATRPKSLPCRSKEMEEITSFIKGSISDDQClGRCMYIHGVPGTGKTISVLSVMKNLKAEVEEGSVSPYCFV 503
Cdd:PTZ00112  742 DKAIRMMQLDVVPKYLPCREKEIKEVHGFLESGIKQSGS-NQILYISGMPGTGKTATVYSVIQLLQHKTKQKLLPSFNVF 820

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 15235420   504 EINGLKLASPENIYSVIYEALSGhrvgwKKALQCLNErFAEGKRIGKEDEKPCILLI----DELDLLVTRNQSVLYNILD 579
Cdd:PTZ00112  821 EINGMNVVHPNAAYQVLYKQLFN-----KKPPNALNS-FKILDRLFNQNKKDNRNVSiliiDEIDYLITKTQKVLFTLFD 894

                         170       180       190       200       210       220       230       240
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 15235420   580 WPTKPNSKLVVLGIANTMDLPEKLLPRISSRMGIQRLCFGPYNHTQLQEIISTRL-NGIDAFEKTAIEFASRKVAAISGD 658
Cdd:PTZ00112  895 WPTKINSKLVLIAISNTMDLPERLIPRCRSRLAFGRLVFSPYKGDEIEKIIKERLeNCKEIIDHTAIQLCARKVANVSGD 974

                         250       260       270       280       290       300
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 15235420   659 ARRALEICRRAAEvadhrlntNKsaKNQLVIMADVEAAIQEMFQAPHIQVMKSVSKLSKIFLTAMVHEL 727
Cdd:PTZ00112  975 IRKALQICRKAFE--------NK--RGQKIVPRDITEATNQLFDSPLTNAINYLPWPFKMFLTCLIVEL 1033

BAH, or Bromo Adjacent Homology domain (also called ELM1 and BAM for Bromo Adjacent Motif). BAH domains have first been described as domains found in the polybromo protein and Yeast Rsc1/Rsc2 (Remodeling of the Structure of Chromatin). They also occur in mammalian DNA methyltransferases and the MTA1 subunits of histone deacetylase complexes. A BAH domain is also found in Yeast Sir3p and in the origin receptor complex protein 1 (Orc1p), where it was found to interact with the N-terminal lobe of the silence information regulator 1 protein (Sir1p), confirming the initial hypothesis that BAH plays a role in protein-protein interactions.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 15235420 240 EKLLSGDLWAARIDKLWKEVDDGVyWIRARWYMIPEETVSGRQPHNLKRELYLTNDFADIEMECILRHCSVKCPKEF--- 316
Cdd:cd04370  16 DSIKSDPPYIARIEELWEDTNGSK-QVKVRWFYRPEETPKGLSPFALRRELFLSDHLDEIPVESIIGKCKVLFVSEFegl 94

                        90       100
                ....*....|....*....|....*...
gi 15235420 317 -SKASNDGDDVFLCEYEYDVHWRSFKRL 343
Cdd:cd04370  95 kQRPNKIDTDDFFCRLAYDPTTKEFKAL 122

orc1/cdc6 family replication initiation protein; Members of this protein family are found exclusively in the archaea. This set of DNA binding proteins shows homology to the origin recognition complex subunit 1/cell division control protein 6 family in eukaryotes. Several members may be found in genome and interact with each other. [DNA metabolism, DNA replication, recombination, and repair]

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 15235420   427 KATLLLATRPKSLPCRSKEMEEITSFIK----GSISDDqclgrcMYIHGVPGTGKTISVLSVMKNLKAEVEEGSVsPYCF 502
Cdd:TIGR02928   5 RDLLEPDYVPDRIVHRDEQIEELAKALRpilrGSRPSN------VFIYGKTGTGKTAVTKYVMKELEEAAEDRDV-RVVT 77

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 15235420   503 VEINGLKLASPENIYSVIYEALSGHRV-----GW------KKALQCLNERFA-------EGKRIGKEDEkpcillideld 564
Cdd:TIGR02928  78 VYVNCQILDTLYQVLVELANQLRGSGEevpttGLstsevfRRLYKELNERGDsliivldEIDYLVGDDD----------- 146

                         170       180       190       200       210       220       230       240
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 15235420   565 llvtrnqSVLYNILDWPTK---PNSKLVVLGIANTMDLPEKLLPRISSRMGIQRLCFGPYNHTQLQEIISTRLNGI---D 638
Cdd:TIGR02928 147 -------DLLYQLSRARSNgdlDNAKVGVIGISNDLKFRENLDPRVKSSLCEEEIIFPPYDAEELRDILENRAEKAfydG 219

                         250       260       270       280       290       300       310       320
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 15235420   639 AFEKTAIEFASRKVAAISGDARRALEICRRAAEVADHRlntnksaKNQLVIMADVEAAiQEmfQAPHIQVMKSVSKL--- 715
Cdd:TIGR02928 220 VLDDGVIPLCAALAAQEHGDARKAIDLLRVAGEIAERE-------GAERVTEDHVEKA-QE--KIEKDRLLELIRGLpth 289

                  ....*...
gi 15235420   716 SKIFLTAM 723
Cdd:TIGR02928 290 SKLVLLAI 297

BAH, or Bromo Adjacent Homology domain, as present in polybromo and yeast RSC1/2. The human polybromo protein (BAF180) is a component of the SWI/SNF chromatin-remodeling complex PBAF. It is thought that polybromo participates in transcriptional regulation. Saccharomyces cerevisiae RSC1 and RSC2 are part of the 15-subunit nucleosome remodeling RSC complex. BAH domains are found in a variety of proteins playing roles in transcriptional silencing and the remodeling of chromatin. It is assumed that in most or all of these instances the BAH domain mediates protein-protein interactions.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 15235420 250 ARIDKLWKEvDDGVYWIRARWYMIPEETVsgrqpHN-----LKRELYLTNDFADIEMECILRHCSVKCPKEFSKASNDG- 323
Cdd:cd04717  24 FRIERLWKD-EDGEKFFFGCWFYRPEETF-----HEptrkfYKNEVFKSPLYETVPVEEIVGKCAVMDVKDYIKGRPTEi 97

                        90       100
                ....*....|....*....|..
gi 15235420 324 --DDVFLCEYEYDVHWRSFKRL 343
Cdd:cd04717  98 seEDVYVCESRYNESAKSFKKI 119

PHD finger found in Remodeling and spacing factor 1 (Rsf-1); Rsf-1, also termed HBV pX-associated protein 8, or Hepatitis B virus X-associated protein alpha (HBxAPalpha), or p325 subunit of RSF chromatin-remodeling complex, is a novel nuclear protein with histone chaperon function. It is a subunit of an ISWI chromatin remodeling complex, remodeling and spacing factor (RSF), and plays a role in mediating ATPase-dependent chromatin remodeling and conferring tumor aggressiveness in common carcinomas. As an ataxia-telangiectasia mutated (ATM)-dependent chromatin remodeler, Rsf-1 facilitates DNA damage checkpoints and homologous recombination repair. It regulates the mitotic spindle checkpoint and chromosome instability through the association with serine/threonine kinase BubR1 (BubR1) and Hepatitis B virus (HBV) X protein (HBx) in the chromatin fraction during mitosis. It also interacts with cyclin E1 and promotes tumor development. Rsf-1 contains a plant homeodomain (PHD) finger.

                        10        20        30        40
                ....*....|....*....|....*....|....*....|....*
gi 15235420 169 CQICFKSD-TNIMIECDDCLGGFHLKCLKPPLKEVPEGDWICQFC 212
Cdd:cd15543   2 CRKCGLSDhPEWILLCDRCDAGYHTACLRPPLMIIPDGNWFCPPC 46

PHD finger found in bromodomain adjacent to zinc finger domain protein BAZ1A and BAZ1B; BAZ1A, also termed ATP-dependent chromatin-remodeling protein, or ATP-utilizing chromatin assembly and remodeling factor 1 (ACF1), or CHRAC subunit ACF1, or Williams syndrome transcription factor-related chromatin-remodeling factor 180 (WCRF180), or WALp1, is a subunit of the conserved imitation switch (ISWI)-family ATP-dependent chromatin assembly and remodeling factor (ACF)/chromatin accessibility complex (CHRAC) chromatin remodeling complex, which is required for DNA replication through heterochromatin. It alters the remodeling properties of the ATPase motor protein sucrose nonfermenting-2 homolog (SNF2H). Moreover, BAZ1A and its complexes play important roles in DNA double-strand break (DSB) repair. It is essential for averting improper gene expression during spermatogenesis. It also regulates transcriptional repression of vitamin D3 receptor-regulated genes. BAZ1B, also termed Tyrosine-protein kinase BAZ1B, or Williams syndrome transcription factor (WSTF), or Williams-Beuren syndrome chromosomal region 10 protein, Williams-Beuren syndrome chromosomal region 9 protein, or WALp2, is a multifunctional protein implicated in several nuclear processes, including replication, transcription, and the DNA damage response. BAZ1B/WSTF, together with the imitation switch (ISWI) ATPase, forms a WSTF-ISWI chromatin remodeling complex (WICH), which transiently associates with the human inactive X chromosome (Xi) during late S-phase prior to BRCA1 and gamma-H2AX. Moreover, BAZ1B/WSTF, SNF2h, and nuclear myosin 1 (NM1) forms the chromatin remodeling complex B-WICH that is involved in regulating rDNA transcription. Both BAZ1A and BAZ1B contain a WAC motif, a DDT domain, BAZ 1 and BAZ 2 motifs, a WAKZ (WSTF/Acf1/KIAA0314/ZK783.4) motif, a plant homeodomain (PHD) finger, and a bromodomain.

                        10        20        30        40
                ....*....|....*....|....*....|....*....|....*
gi 15235420 169 CQICF-KSDTNIMIECDDCLGGFHLKCLKPPLKEVPEGDWICQFC 212
Cdd:cd15544   2 CKVCRkKGDPDNMILCDGCDKAFHLYCLRPALREVPSGDWFCPAC 46

PHD finger 2 found in d4 gene family proteins; The family includes proteins coded by three members of the d4 gene family, DPF1 (neuro-d4), DPF2 (ubi-d4/Requiem), and DPF3 (cer-d4), which function as transcription factors and are involved in transcriptional regulation of genes by changing the condensed/decondensed state of chromatin in the nucleus. DPF2 is ubiquitously expressed and it acts as a transcription factor that may participate in developmentally programmed cell death. DPF1 and DPF3 are expressed predominantly in neural tissues, and they may be involved in the transcription regulation of neuro-specific gene clusters. The d4 family proteins show distinct domain organization with domain 2/3 in the N-terminal region, a Cys2His2 (C2H2) zinc finger or Kruppel-type zinc finger in the central part and two adjacent plant homeodomain (PHD) fingers (d4-domain) in the C-terminal part of the molecule. This model corresponds to the second PHD finger.

                        10        20        30        40
                ....*....|....*....|....*....|....*....|....*
gi 15235420 169 CQICFKSDTN-IMIECDDCLGGFHLKCLKPPLKEVPEGDWICQFC 212
Cdd:cd15530   2 CSLCGTSENDdQLLFCDDCDRGYHMYCLSPPMSEPPEGSWSCHLC 46

ATPase family associated with various cellular activities (AAA); AAA family proteins often perform chaperone-like functions that assist in the assembly, operation, or disassembly of protein complexes.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 15235420   467 MYIHGVPGTGKTISVLSVMKNLKAEveegsvspycFVEINGLKLASpeniysvIYEALSGHRVgwkkalqclNERFAEGK 546
Cdd:pfam00004   1 LLLYGPPGTGKTTLAKAVAKELGAP----------FIEISGSELVS-------KYVGESEKRL---------RELFEAAK 54

                          90       100       110       120       130       140       150
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 15235420   547 RIGKE----DE--KPCILLIDELDLLVTRNQSVLYNILDWPTKPNSKLVVLGIANTMD-LPEKLLPRISSRMGIQR 615
Cdd:pfam00004  55 KLAPCvifiDEidALAGSRGSGGDSESRRVVNQLLTELDGFTSSNSKVIVIAATNRPDkLDPALLGRFDRIIEFPL 130

PHD-finger; PHD folds into an interleaved type of Zn-finger chelating 2 Zn ions in a similar manner to that of the RING and FYVE domains. Several PHD fingers have been identified as binding modules of methylated histone H3.

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|
gi 15235420   169 CQICFKSDT-NIMIECDDCLGGFHLKCLKPPL--KEVPEGDWICQFCEVK 215
Cdd:pfam00628   2 CAVCGKSDDgGELVQCDGCDDWFHLACLGPPLdpAEIPSGEWLCPECKPK 51

PHD finger found in ubiquitin-like PHD and RING finger domain-containing protein UHRF1 and UHRF2; UHRF1 is a unique chromatin effector protein that integrates the recognition of both histone PTMs and DNA methylation. It is essential for cell proliferation and plays a critical role in the development and progression of many human carcinomas, such as laryngeal squamous cell carcinoma (LSCC), gastric cancer (GC), esophageal squamous cell carcinoma (ESCC), colorectal cancer, prostate cancer, and breast cancer. UHRF1 acts as a transcriptional repressor through its binding to histone H3 when it is unmodified at Arg2. Its overexpression in human lung fibroblasts results in downregulation of expression of the tumour suppressor pRB. It also plays a role in transcriptional repression of the cell cycle regulator p21. Moreover, UHRF1-dependent repression of transcription factors can facilitate the G1-S transition. It interacts with Tat-interacting protein of 60 kDa (TIP60) and induces degradation-independent ubiquitination of TIP60. It is also an N-methylpurine DNA glycosylase (MPG)-interacting protein that binds MPG in a p53 status-independent manner in the DNA base excision repair (BER) pathway. In addition, UHRF1 functions as an epigenetic regulator that is important for multiple aspects of epigenetic regulation, including maintenance of DNA methylation patterns and recognition of various histone modifications. UHRF2 was originally identified as a ubiquitin ligase acting as a small ubiquitin-like modifier (SUMO) E3 ligase that enhances zinc finger protein 131 (ZNF131) SUMOylation but does not enhance ZNF131 ubiquitination. It also ubiquitinates PCNP, a PEST-containing nuclear protein. Moreover, UHRF2 functions as a nuclear protein involved in cell-cycle regulation and has been implicated in tumorigenesis. It interacts with cyclins, CDKs, p53, pRB, PCNA, HDAC1, DNMTs, G9a, methylated histone H3 lysine 9, and methylated DNA. It interacts with the cyclin E-CDK2 complex, ubiquitinates cyclins D1 and E1, induces G1 arrest, and is involved in the G1/S transition regulation. Furthermore, UHRF2 is a direct transcriptional target of the transcription factor E2F-1 in the induction of apoptosis. It recruits HDAC1 and binds to methyl-CpG. UHRF2 also participates in the maturation of Hepatitis B virus (HBV) by interacting with the HBV core protein and promoting its degradation. Both UHRF1 and UHRF2 contain an N-terminal ubiquitin-like domain (UBL), a tandem Tudor domain (TTD), a plant homeodomain (PHD) finger, a SET- and RING-associated (SRA) domain, and a C-terminal RING finger.

                        10        20        30        40
                ....*....|....*....|....*....|....*....|....*.
gi 15235420 169 CQICF-KSDTNIMIECDDCLGGFHLKCLKPPLKEVPEGD-WICQFC 212
Cdd:cd15525   2 CHVCGgKQDPEKQLLCDECDMAYHLYCLDPPLTSLPDDDeWYCPDC 47

PHD finger 2 found in class II Chromodomain-Helicase-DNA binding (CHD) proteins; Class II CHD proteins includes chromodomain-helicase-DNA-binding protein CHD3, CHD4, and CHD5, which are nuclear and ubiquitously expressed chromatin remodelling ATPases generally associated with histone deacetylases (HDACs). They are involved in DNA Double Strand Break (DSB) signaling, DSB repair and/or p53-dependent pathways such as apoptosis and senescence, as well as in the maintenance of genomic stability, and/or cancer prevention. They function as subunits of the Nucleosome Remodelling and Deacetylase (NuRD) complex, which is generally associated with gene repression, heterochromatin formation, and overall chromatin compaction. In contrast to the class I CHD enzymes (CHD1 and CHD2), class II CHD proteins lack identifiable DNA-binding domains, but possess a C-terminal coiled-coil region. Moreover, in addition to the tandem chromodomains and a helicase domain, they all harbor tandem plant homeodomain (PHD) zinc fingers involved in the recognition of methylated histone tails. This model corresponds to the second PHD finger.

                        10        20        30        40
                ....*....|....*....|....*....|....*....|....
gi 15235420 169 CQICfkSDTNIMIECDDCLGGFHLKCLKPPLKEVPEGDWICQFC 212
Cdd:cd15532   2 CRVC--KDGGELLCCDGCPSSYHLHCLNPPLAEIPDGDWFCPRC 43

PHD zinc finger; The plant homeodomain (PHD) finger is a C4HC3 zinc-finger-like motif found in nuclear proteins thought to be involved in epigenetics and chromatin-mediated transcriptional regulation. The PHD finger binds two zinc ions using the so-called 'cross-brace' motif and is thus structurally related to the RING finger and the FYVE finger. It is not yet known if PHD fingers have a common molecular function. Several reports suggest that it can function as a protein-protein interacton domain and it was recently demonstrated that the PHD finger of p300 can cooperate with the adjacent BROMO domain in nucleosome binding in vitro. Other reports suggesting that the PHD finger is a ubiquitin ligase have been refuted as these domains were RING fingers misidentified as PHD fingers.

                           10        20        30        40
                   ....*....|....*....|....*....|....*....|....*.
gi 15235420    169 CQICFKS-DTNIMIECDDCLGGFHLKCLKPPLKE-VPEGDWICQFC 212
Cdd:smart00249   2 CSVCGKPdDGGELLQCDGCDRWYHQTCLGPPLLEeEPDGKWYCPKC 47

PHD finger found in bromodomain adjacent to zinc finger domain protein 1B (BAZ1B); BAZ1B, also termed Tyrosine-protein kinase BAZ1B, or Williams syndrome transcription factor (WSTF), or Williams-Beuren syndrome chromosomal region 10 protein, Williams-Beuren syndrome chromosomal region 9 protein, or WALp2, is a multifunctional protein implicated in several nuclear processes, including replication, transcription, and the DNA damage response. BAZ1B/WSTF, together with the imitation switch (ISWI) ATPase, forms a WSTF-ISWI chromatin remodeling complex (WICH), which transiently associates with the human inactive X chromosome (Xi) during late S-phase prior to BRCA1 and gamma-H2AX. Moreover, BAZ1B/WSTF, SNF2h, and nuclear myosin 1 (NM1) forms the chromatin remodeling complex B-WICH that is involved in regulating rDNA transcription. BAZ1B contains a WAC motif, a DDT domain, BAZ 1 and BAZ 2 motifs, a WAKZ (WSTF/Acf1/KIAA0314/ZK783.4) motif, a plant homeodomain (PHD) finger, and a bromodomain.

                        10        20        30        40
                ....*....|....*....|....*....|....*....|....*
gi 15235420 169 CQICF-KSDTNIMIECDDCLGGFHLKCLKPPLKEVPEGDWICQFC 212
Cdd:cd15628   2 CKVCRkKGEDDKLILCDECNQAFHLFCLRPALYEVPDGEWMCPAC 46

PHD finger 5 found in Histone-lysine N-methyltransferase 2C (KMT2C) and PHD finger 4 found in KMT2D; KMT2C, also termed myeloid/lymphoid or mixed-lineage leukemia protein 3 (MLL3), or homologous to ALR protein, is a histone H3 lysine 4 (H3K4) lysine methyltransferase that functions as a circadian factor contributing to genome-scale circadian transcription. It is a component of a large complex that acts as a coactivator of multiple transcription factors, including the bile acid (BA)-activated nuclear receptor, farnesoid X receptor (FXR), a critical player in BA homeostasis. The MLL3 complex is essential for p53 transactivation of small heterodimer partner (SHP). KMT2C is also a part of activating signal cointegrator-2 (ASC-2)-containing complex (ASCOM) that contains the transcriptional coactivator nuclear receptor coactivator 6 (NCOA6), KMT2C and its paralog MLL4. The ASCOM complex is critical for nuclear receptor (NR) activation of bile acid transporter genes and is down regulated in cholestasis. KMT2D, also termed ALL1-related protein (ALR), is encoded by the gene that was named MLL4, a fourth human homolog of Drosophila trithorax, located on chromosome 12. It enzymatically generates trimethylated histone H3 Lysine 4 (H3K4me3). It plays an essential role in differentiating the human pluripotent embryonal carcinoma cell line NTERA-2 clone D1 (NT2/D1) stem cells by activating differentiation-specific genes, such as HOXA1-3 and NESTIN. KMT2D is also a part of ASCOM. Both KMT2C and KMT2D contain the catalytic domain SET, several plant homeodomain (PHD) fingers, extended PHD (ePHD) fingers, Cys2HisCys5HisCys2His, a RING finger, an HMG (high-mobility group)-binding motif, and two FY-rich regions. This model corresponds to the fifth PHD finger of KMT2C and the fourth PHD finger of KMT2D.

                        10        20        30        40
                ....*....|....*....|....*....|....*....|....*
gi 15235420 169 CQICFK-SDTNIMIECDDCLGGFHLKCLKPPLKEVPEGDWICQFC 212
Cdd:cd15513   2 CEGCGKaSDESRLLLCDDCDISYHTYCLDPPLQTVPKGGWKCKWC 46

PHD finger superfamily; The PHD finger superfamily includes a canonical plant homeodomain (PHD) finger typically characterized as Cys4HisCys3, and a non-canonical extended PHD finger, characterized as Cys2HisCys5HisCys2His. Variations include the RAG2 PHD finger characterized by Cys3His2Cys2His and the PHD finger 5 found in nuclear receptor-binding SET domain-containing proteins characterized by Cys4HisCys2His. The PHD finger is also termed LAP (leukemia-associated protein) motif or TTC (trithorax consensus) domain. Single or multiple copies of PHD fingers have been found in a variety of eukaryotic proteins involved in the control of gene transcription and chromatin dynamics. PHD fingers can recognize the unmodified and modified histone H3 tail, and some have been found to interact with non-histone proteins. They also function as epigenome readers controlling gene expression through molecular recruitment of multi-protein complexes of chromatin regulators and transcription factors. The PHD finger domain SF is structurally similar to the RING and FYVE_like superfamilies.

                        10        20        30        40
                ....*....|....*....|....*....|....*....|....*..
gi 15235420 169 CQICFKS--DTNIMIECDDCLGGFHLKCLKPPLKE-VPEGDWICQFC 212
Cdd:cd15489   2 CIVCGKGgdLGGELLQCDGCGKWFHADCLGPPLSSfVPNGKWICPVC 48

PHD finger 1 found in Lysine-specific demethylase KDM5A, KDM5B, KDM5C, KDM5D and similar proteins; The JARID subfamily within the JmjC proteins includes Lysine-specific demethylase KDM5A, KDM5B, KDM5C, KDM5D and a Drosophila homolog, protein little imaginal discs (Lid). KDM5A was originally identified as a retinoblastoma protein (Rb)-binding partner and its inactivation may be important for Rb to promote differentiation. It is involved in transcription through interacting with TBP, p107, nuclear receptors, Myc, Sin3/HDAC, Mad1, RBP-J, CLOCK and BMAL1. KDM5B has a restricted expression pattern in the testis, ovary, and transiently in the mammary gland of the pregnant female and has been shown to be upregulated in breast cancer, prostate cancer, and lung cancer, suggesting a potential role in tumorigenesis. Both KDM5A and KDM5B function as trimethylated histone H3 lysine 4 (H3K4me3) demethylases. KDM5C is a H3K4 trimethyl-histone demethylase that catalyzes demethylation of H3K4me3 and H3K4me2 to H3K4me1. It plays a role in neuronal survival and dendrite development. KDM5C defects are associated with X-linked mental retardation (XLMR). KDM5D is a male-specific antigen that shows a demethylase activity specific for di- and tri-methylated histone H3K4 (H3K4me2 and H3K4me3), and has a male-specific function as a histone H3K4 demethylase by recruiting a meiosis-regulatory protein, MSH5, to condensed DNA. KDM5D directly interacts with a polycomb-like protein Ring6a/MBLR, and plays a role in regulation of transcriptional initiation through H3K4 demethylation. This family also includes Drosophila melanogaster protein little imaginal discs (Lid) that functions as a JmjC-dependent H3K4me3 demethylase, which is required for dMyc-induced cell growth. It positively regulates Hox gene expression in S2 cells. Members in this family contain the catalytic JmjC domain, JmjN, the BRIGHT domain, which is an AT-rich interacting domain (ARID), and a Cys5HisCys2 zinc finger, as well as two or three plant homeodomain (PHD) fingers. This model corresponds to the first PHD finger.

                        10        20        30        40
                ....*....|....*....|....*....|....*....|....*
gi 15235420 169 CQIC-FKSDTNIMIECDDCLGGFHLKCLKPPLKEVPEGDWICQFC 212
Cdd:cd15515   2 CQVCgRGDDEDKLLLCDGCDDSYHTFCLIPPLPDIPPGDWRCPKC 46

PHD finger 2 found in Histone-lysine N-methyltransferase 2C (KMT2C) and 2D (KMT2D); KMT2C, also termed myeloid/lymphoid or mixed-lineage leukemia protein 3 (MLL3) or homologous to ALR protein, is a histone H3 lysine 4 (H3K4) lysine methyltransferase that functions as a circadian factor contributing to genome-scale circadian transcription. It is a component of a large complex that acts as a coactivator of multiple transcription factors, including the bile acid (BA)-activated nuclear receptor, farnesoid X receptor (FXR), a critical player in BA homeostasis. The MLL3 complex is essential for p53 transactivation of small heterodimer partner (SHP). KMT2C is also a part of activating signal cointegrator-2 (ASC-2)-containing complex (ASCOM) that contains the transcriptional coactivator nuclear receptor coactivator 6 (NCOA6), KMT2C and its paralog MLL4. The ASCOM complex is critical for nuclear receptor (NR) activation of bile acid transporter genes and is down regulated in cholestasis. KMT2D, also termed ALL1-related protein (ALR), is encoded by the gene that was named MLL4, a fourth human homolog of Drosophila trithorax, located on chromosome 12. It enzymatically generates trimethylated histone H3 Lysine 4 (H3K4me3). It plays an essential role in differentiating the human pluripotent embryonal carcinoma cell line NTERA-2 clone D1 (NT2/D1) stem cells by activating differentiation-specific genes, such as HOXA1-3 and NESTIN. KMT2D is also a part of ASCOM. Both KMT2C and KMT2D contain the catalytic domain SET, five plant homeodomain (PHD) fingers, two extended PHD (ePHD) fingers, Cys2HisCys5HisCys2His, a RING finger, an HMG (high-mobilitygroup)-binding motif, and two FY-rich regions. This model corresponds to the second PHD finger.

                        10        20        30        40
                ....*....|....*....|....*....|....*....|....*
gi 15235420 169 CQICFKSDTNI-MIECDDCLGGFHLKCLKPPLKEVPEGDWICQFC 212
Cdd:cd15510   2 CQACRQPGDDTkMLVCETCDKGYHTSCLRPVMSSIPKYGWKCKNC 46

BAH, or Bromo Adjacent Homology domain, as present in mammalian BAHCC1 and similar proteins. BAHCC1 stands for BAH domain and coiled-coil containing 1. BAH domains are found in a variety of proteins playing roles in transcriptional silencing and the remodeling of chromatin. It is assumed that in most or all of these instances the BAH domain mediates protein-protein interactions.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 15235420 250 ARIDKLWkEVDDGVYWIRARWYMIPEETVSGRQPHNLKRELYLTNDFADIEMECILRHCSVKCPKEFSKASN------DG 323
Cdd:cd04714  24 ARIESLW-EDPEGNMVVRVKWYYRPEETKGGRKPNHGEKELFASDHQDENSVQTIEHKCYVLTFAEYERLARvkkkpqDG 102

                        90
                ....*....|.
gi 15235420 324 DDVFLCEYEYD 334
Cdd:cd04714 103 VDFYYCAGTYN 113

PHD finger 2 found in Histone-lysine N-methyltransferase 2D (KMT2D); KMT2D, also termed ALL1-related protein (ALR), is encoded by the gene that was named myeloid/lymphoid or mixed-lineage leukemia 4 (MLL4), a fourth human homolog of Drosophila trithorax, located on chromosome 12. KMT2D enzymatically generates trimethylated histone H3 Lys 4 (H3K4me3). It plays an essential role in differentiating the human pluripotent embryonal carcinoma cell line NTERA-2 clone D1 (NT2/D1) stem cells by activating differentiation-specific genes, such asHOXA1-3 and NESTIN. It is also a part of activating signal cointegrator-2 (ASC-2)-containing complex (ASCOM) that contains the transcriptional coactivator nuclear receptor coactivator 6 (NCOA6), KMT2C and KMT2D. The ASCOM complex is critical for nuclear receptor (NR) activation of bile acid transporter genes and is down regulated in cholestasis. KMT2D contains the catalytic domain SET, five plant homeodomain (PHD) fingers, two extended PHD (ePHD) fingers, Cys2HisCys5HisCys2His, a RING finger, an HMG (high-mobility group)-binding motif, and two FY-rich regions. This model corresponds to the second PHD finger.

                        10        20        30        40
                ....*....|....*....|....*....|....*....|....*
gi 15235420 169 CQICFK-SDTNIMIECDDCLGGFHLKCLKPPLKEVPEGDWICQFC 212
Cdd:cd15595   2 CQTCRKpGEDSKMLVCEACDKGYHTFCLKPAMESLPTDSWKCKAC 46

PHD finger 1 found in lysine-specific demethylase 5B (KDM5B); KDM5B (also termed Cancer/testis antigen 31 (CT31), Histone demethylase JARID1B, Jumonji/ARID domain-containing protein 1B (JARID1B), PLU-1, or retinoblastoma-binding protein 2 homolog 1 (RBP2-H1 or RBBP2H1A)) is a member of the JARID subfamily within the JmjC proteins. It has a restricted expression pattern in the testis, ovary, and transiently in the mammary gland of pregnant females and has been shown to be upregulated in breast cancer, prostate cancer, and lung cancer, suggesting a potential role in tumorigenesis. KDM5B acts as a histone demethylase that catalyzes the removal of trimethylation of lysine 4 on histone H3 (H3K4me3), induced by polychlorinated biphenyls (PCBs). It also mediates demethylation of H3K4me2 and H3K4me1. Moreover, KDM5B functions as a negative regulator of hematopoietic stem cell (HSC) self-renewal and progenitor cell activity. KDM5B has also been shown to interact with the DNA binding transcription factors BF-1 and PAX9, as well as TIEG1/KLF10 (transforming growth factor-beta inducible early gene-1/Kruppel-like transcription factor 10), and possibly function as a transcriptional corepressor. KDM5B contains the catalytic JmjC domain, JmjN, the BRIGHT domain, which is an AT-rich interacting domain (ARID), and a Cys5HisCys2 zinc finger, as well as three plant homeodomain (PHD) fingers. This model corresponds to the first PHD finger.

                        10        20        30        40
                ....*....|....*....|....*....|....*....|....*
gi 15235420 169 CQICFK-SDTNIMIECDDCLGGFHLKCLKPPLKEVPEGDWICQFC 212
Cdd:cd15603   2 CLVCGSgNDEDRLLLCDGCDDSYHTFCLIPPLHDVPKGDWRCPKC 46

PHD finger 1 found in class II Chromodomain-Helicase-DNA binding (CHD) proteins; Class II CHD proteins includes chromodomain-helicase-DNA-binding protein CHD3, CHD4, and CHD5, which are nuclear and ubiquitously expressed chromatin remodelling ATPases generally associated with histone deacetylases (HDACs). They are involved in DNA Double Strand Break (DSB) signaling, DSB repair and/or p53-dependent pathways such as apoptosis and senescence, as well as in the maintenance of genomic stability, and/or cancer prevention. They function as subunits of the Nucleosome Remodelling and Deacetylase (NuRD) complex, which is generally associated with gene repression, heterochromatin formation, and overall chromatin compaction. In contrast to the class I CHD enzymes (CHD1 and CHD2), class II CHD proteins lack identifiable DNA-binding domains, but possess a C-terminal coiled-coil region. Moreover, in addition to the tandem chromodomains and a helicase domain, they all harbor tandem plant homeodomain (PHD) zinc fingers involved in the recognition of methylated histone tails. This model corresponds to the first PHD finger.

                        10        20        30        40
                ....*....|....*....|....*....|....*....|....
gi 15235420 169 CQICFKSDTNIMieCDDCLGGFHLKCLKPPLKEVPEGDWICQFC 212
Cdd:cd15531   2 CEVCQQGGEIIL--CDTCPRAYHLVCLDPELEKAPEGKWSCPHC 43

PHD finger 1 found in Lysine-specific demethylase 5C (KDM5C) and 5D (KDM5D); The family includes KDM5C and KDM5D, both of which belong to the JARID subfamily within the JmjC proteins. KDM5C (also termed Histone demethylase JARID1C, Jumonji/ARID domain-containing protein 1C, SmcX, or Xe169) is a H3K4 trimethyl-histone demethylase that catalyzes demethylation of H3K4me3 and H3K4me2 to H3K4me1. It plays a role in neuronal survival and dendrite development. KDM5C defects are associated with X-linked mental retardation (XLMR). KDM5D (also termed Histocompatibility Y antigen (H-Y), Histone demethylase JARID1D, Jumonji/ARID domain-containing protein 1D, or SmcY) is a male-specific antigen that shows a demethylase activity specific for di- and tri-methylated histone H3K4 (H3K4me3 andH3K4me2), and has a male-specific function as a histone H3K4 demethylase by recruiting a meiosis-regulatory protein, MSH5, to condensed DNA. KDM5D directly interacts with a polycomb-like protein Ring6a/MBLR, and plays a role in regulation of transcriptional initiation through H3K4 demethylation. Both KDM5C and KDM5D contain the catalytic JmjC domain, JmjN, the BRIGHT domain, which is an AT-rich interacting domain (ARID), and a Cys5HisCys2 zinc finger, as well as two plant homeodomain (PHD) fingers. This model corresponds to the first PHD finger.

                        10        20        30        40
                ....*....|....*....|....*....|....*....|....*
gi 15235420 169 CQICFKSDTN-IMIECDDCLGGFHLKCLKPPLKEVPEGDWICQFC 212
Cdd:cd15604   2 CRMCSRGDEDdKLLLCDGCDDNYHTFCLLPPLPEPPKGIWRCPKC 46

PHD finger found in the transcriptional intermediary factor 1 (TIF1) family and similar proteins; The TIF1 family of transcriptional cofactors includes TIF1alpha (TRIM24), TIF1beta (TRIM28), TIF1gamma (TRIM33), and TIF1delta (TRIM66), which are characterized by an N-terminal RING-finger B-box coiled-coil (RBCC/TRIM) motif and plant homeodomain (PHD) finger followed by a bromodomain in the C-terminal region. TIF1 proteins couple chromatin modifications to transcriptional regulation, signaling, and tumor suppression. They exert a deacetylase-dependent silencing effect when tethered to a promoter region. TIF1alpha, TIF1beta, and TIF1delta can homodimerize and contain a PXVXL motif necessary and sufficient for heterochromatin protein 1(HP1) binding. TIF1alpha and TIF1beta bind nuclear receptors and Kruppel-associated boxes (KRAB) specifically and respectively. In contrast, TIF1delta appears to lack nuclear receptor- and KRAB-binding activity. Moreover, TIF1delta is specifically involved in heterochromatin-mediated gene silencing during postmeiotic phases of spermatogenesis. TIF1gamma is structurally closely related to TIF1alpha and TIF1beta, but has very little functional features in common with them. It does not interact with the KRAB silencing domain of KOX1 or the heterochromatinic proteins HP1alpha, beta, and gamma. It cannot bind to nuclear receptors (NRs). This family also includes Sp100/Sp140 family proteins, the nuclear body SP100 and SP140. Sp110 is a leukocyte-specific component of the nuclear body. It may function as a nuclear hormone receptor transcriptional coactivator that may play a role in inducing differentiation of myeloid cells. It is also involved in resisting intracellular pathogens and functions as an important drug target for preventing intracellular pathogen diseases, such as tuberculosis, hepatic veno-occlusive disease, and intracellular cancers. SP140 is an interferon inducible nuclear leukocyte-specific protein involved in primary biliary cirrhosis and a risk factor in chronic lymphocytic leukemia. It is also implicated in innate immune response to human immunodeficiency virus type 1 (HIV-1) by binding to the virus viral infectivity factor (Vif) protein. Both Sp110 and Sp140 contain a SAND domain, a plant homeodomain (PHD) finger, and a bromodomain (BRD).

                        10        20        30
                ....*....|....*....|....*....|
gi 15235420 183 CDDCLGGFHLKCLKPPLKEVPEGDWICQFC 212
Cdd:cd15541  14 CDKCPRVFHLDCHIPPIPEFPSGEWSCSLC 43

PHD finger 1 found in PHD finger protein 12 (PHF12); PHF12, also termed PHD factor 1 (Pf1), is a plant homeodomain (PHD) zinc finger-containing protein that bridges the transducin-like enhancer of split (TLE) corepressor to the mSin3A-histone deacetylase (HDAC)-complex, and further represses transcription at targeted genes. PHF12 also interacts with MRG15 (mortality factor-related genes on chromosome 15), a member of the mortality factor (MORF) family of proteins implicated in regulating cellular senescence. PHF12 contains two plant-homeodomain (PHD) zinc fingers followed by a polybasic region. The PHD fingers function downstream of phosphoinositide signaling triggered by the interaction between polybasic regions and phosphoinositides. This model corresponds to the first PHD finger.

                        10        20        30
                ....*....|....*....|....*....|..
gi 15235420 183 CDDCLGGFHLKCLKPPLKE--VPEGDWICQFC 212
Cdd:cd15533  14 CDRCPASFHLQCCNPPLDEedLPPGEWLCHRC 45

PHD finger found in PHD finger protein 21B (PHF21B); PHF21B is a plant homeodomain (PHD) finger-containing protein whose biological function remains unclear. It shows high sequence similarity with PHF21A, which is associated with LSD1, a lysine (K)-specific histone demethylase and inhibits LSD1-mediated histone demethylation in vitro. PHD fingers can recognize the unmodified and modified histone H3 tail, and some have been found to interact with non-histone proteins.

                        10        20        30        40
                ....*....|....*....|....*....|....*....|....
gi 15235420 169 CQICfKSDTNIMiECDDCLGGFHLKCLKPPLKEVPEGDWICQFC 212
Cdd:cd15524   2 CAAC-KRGGNLQ-PCGTCPRAYHLDCLDPPLKTAPKGVWVCPKC 43

PHD finger found in transcription initiation factor TFIID subunit 3 (TAF3); TAF3 (also termed 140 kDa TATA box-binding protein-associated factor, TBP-associated factor 3, transcription initiation factor TFIID 140 kDa subunit (TAF140), or TAFII-140, is an integral component of TFIID) is a general initiation factor (GTF) that plays a key role in preinitiation complex (PIC) assembly through core promoter recognition. The interaction of H3K4me3 with TAF3 directs global TFIID recruitment to active genes, which regulates gene-selective functions of p53 in response to genotoxic stress. TAF3 is highly enriched in embryonic stem cells and is required for endoderm lineage differentiation and prevents premature specification of neuroectoderm and mesoderm. Moreover, TAF3, along with TRF3, forms a complex that is essential for myogenic differentiation. TAF3 contains a plant homeodomain (PHD) finger. This family also includes Drosophila melanogaster BIP2 (Bric-a-brac interacting protein 2) protein, which functions as an interacting partner of D. melanogaster p53 (Dmp53).

                        10        20        30        40
                ....*....|....*....|....*....|....*....|....*..
gi 15235420 169 CQICFKSDT-NIMIECDDCLGGFHLKCLKppLKEVP--EGDWICQFC 212
Cdd:cd15522   2 CPICKKPDDgSPMIGCDECDDWYHWECVG--ITDEPpeEDDWFCPKC 46