BCL2-associated athanogene 6; This domain is found in large proline-rich protein BAG6 protein. It has a conserved SDL sequence motif. Human BAG6 is an ATP-independent molecular chaperone preventing the aggregation of misfolded and hydrophobic patches-containing proteins. It functions as part of a cytosolic protein quality control complex, the BAG6/BAT3 complex, which maintains these client proteins in a soluble state and participates to their proper delivery to the endoplasmic reticulum or alternatively can promote their sorting to the proteasome where they undergo degradation.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 637274141   220 YVEVLGELRGVENRLQPFLQRYEEILGTAGSADYNNNTEGREEDQRIINLVGESLRLLGNTFVTLSDLRCNLSCNAPRHL 299
Cdd:pfam12057    1 LAELLQELRRVEERLRPFLERYHMILGEAPTADYNNNTEGREEDQRILDLVSEALHLLSHAYHALSDLRLNLSQPPPRHL 80

                           90       100       110
                   ....*....|....*....|....*....|....*.
gi 637274141   300 HVVRPMSHYTAPMVLQQaaIPIQINVGTTVTMTGNG 335
Cdd:pfam12057   81 HVVRPILHYHSPVLLPG--IPIQVNLGTTVTPPSNN 114

transcriptional regulator ICP4; Provisional

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 637274141  330 TMTGNGSRGAQTSSEGSTASQTSPPAQPGTSTPPDA----------GRPTEGSPPAASSPGAAPTQTQGSQTGHPRVIRI 399
Cdd:PHA03307   99 SPAREGSPTPPGPSSPDPPPPTPPPASPPPSPAPDLsemlrpvgspGPPPAASPPAAGASPAAVASDAASSRQAALPLSS 178

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 637274141  400 SHQTVEPVVMmhmniQDSSSPMGGSGTGGAPPAGTPGPIGHTPGMGGAPhMPLPS--LPPEFMQAVAHQITQQAMAAAAS 477
Cdd:PHA03307  179 PEETARAPSS-----PPAEPPPSTPPAAASPRPPRRSSPISASASSPAP-APGRSaaDDAGASSSDSSSSESSGCGWGPE 252

                         170       180       190       200       210       220       230       240
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 637274141  478 AAAGQQVPSFQSAPTRVMIARPSAPSVRPTHPGSPQAPGQGPpslggnASLAQMISGLVGQLLMQPVIVAQGSGTTASAP 557
Cdd:PHA03307  253 NECPLPRPAPITLPTRIWEASGWNGPSSRPGPASSSSSPRER------SPSPSPSSPGSGPAPSSPRASSSSSSSRESSS 326

                         250       260
                  ....*....|....*....|.
gi 637274141  558 SSvNTQATFSTSNSASPPTAS 578
Cdd:PHA03307  327 SS-TSSSSESSRGAAVSPGPS 346

BCL2-associated athanogene 6; This domain is found in large proline-rich protein BAG6 protein. It has a conserved SDL sequence motif. Human BAG6 is an ATP-independent molecular chaperone preventing the aggregation of misfolded and hydrophobic patches-containing proteins. It functions as part of a cytosolic protein quality control complex, the BAG6/BAT3 complex, which maintains these client proteins in a soluble state and participates to their proper delivery to the endoplasmic reticulum or alternatively can promote their sorting to the proteasome where they undergo degradation.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 637274141   220 YVEVLGELRGVENRLQPFLQRYEEILGTAGSADYNNNTEGREEDQRIINLVGESLRLLGNTFVTLSDLRCNLSCNAPRHL 299
Cdd:pfam12057    1 LAELLQELRRVEERLRPFLERYHMILGEAPTADYNNNTEGREEDQRILDLVSEALHLLSHAYHALSDLRLNLSQPPPRHL 80

                           90       100       110
                   ....*....|....*....|....*....|....*.
gi 637274141   300 HVVRPMSHYTAPMVLQQaaIPIQINVGTTVTMTGNG 335
Cdd:pfam12057   81 HVVRPILHYHSPVLLPG--IPIQVNLGTTVTPPSNN 114

Ubiquitin homologues; Ubiquitin-mediated proteolysis is involved in the regulated turnover of proteins required for controlling cell cycle progression

                            10        20        30        40        50        60        70
                    ....*....|....*....|....*....|....*....|....*....|....*....|....*....|..
gi 637274141      7 LEVMVKTLDSQTRTFTVEEEITVKEFKEHIASSVNIPAEKQRLIYQGRVLQDDKKLKEYNVG-GKVIHLVER 77
Cdd:smart00213    1 IELTVKTLDGKTITLEVKPSDTVSELKEKIAELTGIPPEQQRLIYKGKVLEDDRTLADYGIQdGSTIHLVLR 72

ubiquitin; Provisional

                          10        20        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 637274141    7 LEVMVKTLDSQTRTFTVEEEITVKEFKEHIASSVNIPAEKQRLIYQGRVLQDDKKLKEYNV-GGKVIHLV 75
Cdd:PTZ00044    1 MQILIKTLTGKKQSFNFEPDNTVQQVKMALQEKEGIDVKQIRLIYSGKQMSDDLKLSDYKVvPGSTIHMV 70

transcriptional regulator ICP4; Provisional

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 637274141  330 TMTGNGSRGAQTSSEGSTASQTSPPAQPGTSTPPDA----------GRPTEGSPPAASSPGAAPTQTQGSQTGHPRVIRI 399
Cdd:PHA03307   99 SPAREGSPTPPGPSSPDPPPPTPPPASPPPSPAPDLsemlrpvgspGPPPAASPPAAGASPAAVASDAASSRQAALPLSS 178

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 637274141  400 SHQTVEPVVMmhmniQDSSSPMGGSGTGGAPPAGTPGPIGHTPGMGGAPhMPLPS--LPPEFMQAVAHQITQQAMAAAAS 477
Cdd:PHA03307  179 PEETARAPSS-----PPAEPPPSTPPAAASPRPPRRSSPISASASSPAP-APGRSaaDDAGASSSDSSSSESSGCGWGPE 252

                         170       180       190       200       210       220       230       240
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 637274141  478 AAAGQQVPSFQSAPTRVMIARPSAPSVRPTHPGSPQAPGQGPpslggnASLAQMISGLVGQLLMQPVIVAQGSGTTASAP 557
Cdd:PHA03307  253 NECPLPRPAPITLPTRIWEASGWNGPSSRPGPASSSSSPRER------SPSPSPSSPGSGPAPSSPRASSSSSSSRESSS 326

                         250       260
                  ....*....|....*....|.
gi 637274141  558 SSvNTQATFSTSNSASPPTAS 578
Cdd:PHA03307  327 SS-TSSSSESSRGAAVSPGPS 346

BCL2-associated athanogene 6; This domain is found in large proline-rich protein BAG6 protein. It has a conserved SDL sequence motif. Human BAG6 is an ATP-independent molecular chaperone preventing the aggregation of misfolded and hydrophobic patches-containing proteins. It functions as part of a cytosolic protein quality control complex, the BAG6/BAT3 complex, which maintains these client proteins in a soluble state and participates to their proper delivery to the endoplasmic reticulum or alternatively can promote their sorting to the proteasome where they undergo degradation.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 637274141   220 YVEVLGELRGVENRLQPFLQRYEEILGTAGSADYNNNTEGREEDQRIINLVGESLRLLGNTFVTLSDLRCNLSCNAPRHL 299
Cdd:pfam12057    1 LAELLQELRRVEERLRPFLERYHMILGEAPTADYNNNTEGREEDQRILDLVSEALHLLSHAYHALSDLRLNLSQPPPRHL 80

                           90       100       110
                   ....*....|....*....|....*....|....*.
gi 637274141   300 HVVRPMSHYTAPMVLQQaaIPIQINVGTTVTMTGNG 335
Cdd:pfam12057   81 HVVRPILHYHSPVLLPG--IPIQVNLGTTVTPPSNN 114

Ubiquitin homologues; Ubiquitin-mediated proteolysis is involved in the regulated turnover of proteins required for controlling cell cycle progression

                            10        20        30        40        50        60        70
                    ....*....|....*....|....*....|....*....|....*....|....*....|....*....|..
gi 637274141      7 LEVMVKTLDSQTRTFTVEEEITVKEFKEHIASSVNIPAEKQRLIYQGRVLQDDKKLKEYNVG-GKVIHLVER 77
Cdd:smart00213    1 IELTVKTLDGKTITLEVKPSDTVSELKEKIAELTGIPPEQQRLIYKGKVLEDDRTLADYGIQdGSTIHLVLR 72

ubiquitin-like (Ubl) domain found in ubiquitin and ubiquitin-like Ubl proteins; Ubiquitin-like (Ubl) proteins have a similar ubiquitin (Ub) beta-grasp fold and attach to other proteins in a Ubl manner but with biochemically distinct roles. Ub and Ubl proteins conjugate and deconjugate via ligases and peptidases to covalently modify target polypeptides. Some Ubl domains have adaptor roles in Ub-signaling by mediating protein-protein interaction. Prokaryotic sulfur carrier proteins are Ub-related proteins that can be activated in an ATP-dependent manner. Polyubiquitination signals for a diverse set of cellular events via different isopeptide linkages formed between the C terminus of one ubiquitin (Ub) and the epsilon-amine of K6, K11, K27, K29, K33, K48, or K63 of a second Ub. One of these seven lysine residues (K27, Ub numbering) is conserved in this Ubl_ubiquitin_like family. K27-linked Ub chains are versatile and can be recognized by several downstream receptor proteins. K27 has roles beyond chain linkage, such as in Ubl NEDD8 (which contains many of the same lysines (K6, K11, K27, K33, K48) as Ub) where K27 has a role (other than conjugation) in the mechanism of protein neddylation.

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 637274141    9 VMVKTLDSQTRTFTVEEEITVKEFKEHIASSVNIPAEKQRLIYQGRVLQDDKKLKEYNVG-GKVIHLV 75
Cdd:cd17039     1 ITVKTLDGKTYTVEVDPDDTVADLKEKIEEKTGIPVEQQRLIYNGKELKDDKTLSDYGIKdGSTIHLV 68

ubiquitin-like (Ubl) domain found in the Rad23 protein family; The Rad23 family includes the yeast nucleotide excision repair (NER) proteins, Rad23p (in Saccharomyces cerevisiae) and Rhp23p (in Schizosaccharomyces pombe), their mammalian orthologs HR23A and HR23B, and putative DNA repair proteins from plants. Rad23 proteins play dual roles in DNA repair as well as in proteosomal degradation. They have affinity for both the proteasome and ubiquitinylated proteins and participate in translocating polyubiquitinated proteins to the proteasome. Rad23 proteins carry an ubiquitin-like (Ubl) domain with a beta-grasp Ubl fold, and two ubiquitin-associated (UBA) domains, as well as a xeroderma pigmentosum group C (XPC) protein-binding domain. The Ubl domain is responsible for the binding to proteasome. The UBA domains are important for binding of ubiquitin (Ub) or multi-ubiquitinated substrates, which suggests Rad23 proteins might be involved in certain pathways of Ub metabolism. Both the Ubl domain and the XPC-binding domain are necessary for efficient NER function of Rad23 proteins.

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|
gi 637274141    9 VMVKTLDSQTRTFTVEEEITVKEFKEHIASSVN-IPAEKQRLIYQGRVLQDDKKLKEYNV 67
Cdd:cd01805     3 ITFKTLQQQTFEIEVEPSDTVLELKEKIEQEQGdFPASGQKLIYSGKVLKDDKTLSEYNI 62

ubiquitin-like (Ubl) domain found in eukaryotic protein linking integrin-associated protein (IAP, also known as CD47) with cytoskeleton (PLIC) proteins; The PLIC proteins (or ubiquilins) family contains human homologs of the yeast ubiquitin-like (Ubl) Dsk2 protein, PLIC-1 (also termed ubiquilin-1), PLIC-2 (also termed ubiquilin-2, or Chap1), PLIC-3 (also termed ubiquilin-3) and PLIC-4 (also termed ubiquilin-4, ataxin-1 interacting ubiquitin-like protein, A1Up, connexin43-interacting protein of 75 kDa, or CIP75), and mouse PLIC proteins. They are ubiquitin (Ub)-binding adaptor proteins involved in all protein degradation pathways through delivering ubiquitinated substrates to proteasomes. They also promote autophagy-dependent cell survival during nutrient starvation. PLIC-1 regulates the function of the thrombospondin receptor CD47 and G protein signaling. It plays a role in TLR4-mediated signaling through interacting with the Toll/interleukin-1 receptor (TIR) domain of TLR4. It also inhibits the TLR3-Trif antiviral pathway by reducing the abundance of Trif. Moreover, PLIC-1 binds to gamma-aminobutyric acid receptors (GABAARs) and modulates the Ub-dependent, proteasomal degradation of GABAARs. Furthermore, PLIC-1 acts as a molecular chaperone regulating amyloid precursor protein (APP) biosynthesis, trafficking, and degradation by stimulating K63-linked polyubiquitination of lysine 688 in the APP intracellular domain. In addition, PLIC-1 is involved in the protein aggregation-stress pathway via associating with the Ub-interacting motif (UIM) proteins ataxin 3, HSJ1a, and epidermal growth factor substrate 15 (EPS15). PLIC-2 is a protein that binds the ATPase domain of the HSP70-like Stch protein. It functions as a negative regulator of G protein-coupled receptor (GPCR) endocytosis. It also involved in amyotrophic lateral sclerosis (ALS)-related dementia. PLIC-3 is encoded by UbiquilinN3, a testis-specific gene. It shows high sequence similarity with the Xenopus protein XDRP1, a nuclear phosphoprotein that binds to the N-terminus of cyclin A and inhibits Ca2+-induced degradation of cyclin A, but not cyclin B. PLIC-4 is an ubiquitin-like (Ubl) nuclear protein that interacts with ataxin-1 and further links ataxin-1 with the chaperone and Ub-proteasome pathways. It also binds to the non-ubiquitinated gap junction protein connexin43 (Cx43) and regulates the turnover of Cx43 through the proteasomal pathway. PLIC proteins contain an N-terminal Ubl domain that is responsible for the binding of Ub-interacting motifs (UIMs) expressed by proteasomes and endocytic adaptors, and C-terminal Ub-associated (UBA) domain that interacts with Ub chains present on proteins destined for proteasomal degradation. In addition, mammalian PLIC2 proteins have an extra collagen-like motif region, which is absent in other PLIC proteins and the yeast Dsk2 protein.

                          10        20        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|..
gi 637274141    5 ENLEVMVKTLDSQtRTFTVEEEITVKEFKEHIASSVNIPAEKQRLIYQGRVLQDDKKLKEYNV-GGKVIHLV 75
Cdd:cd01808     1 SIIKVTVKTPKEK-EDFEVPEDSSVKEFKEEISKKFKAPVEQLVLIFAGKILKDQDTLSQHGIkDGLTVHLV 71

ubiquitin; Provisional

                          10        20        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 637274141    7 LEVMVKTLDSQTRTFTVEEEITVKEFKEHIASSVNIPAEKQRLIYQGRVLQDDKKLKEYNV-GGKVIHLV 75
Cdd:PTZ00044    1 MQILIKTLTGKKQSFNFEPDNTVQQVKMALQEKEGIDVKQIRLIYSGKQMSDDLKLSDYKVvPGSTIHMV 70

ubiquitin-like (Ubl) domain found in ubiquitin-like proteins UBL4A and similar proteins; UBL4A, also termed GdX, is a ubiquitously expressed ubiquitin-like (Ubl) protein that forms a complex with partner proteins and participates in the protein processing through endoplasmic reticulum (ER), acting as a chaperone. As a key component of the BCL2-associated athanogene 6 (BAG6) chaperone complex, UBL4A plays a role in mediating DNA damage signaling and cell death. UBL4A also regulates insulin-induced Akt plasma membrane translocation through promotion of Arp2/3-dependent actin branching. Moreover, UBL4A specifically stabilizes the TC45/STAT3 association and promotes dephosphorylation of STAT3 to repress tumorigenesis. UBL4B is testis-specific, and encoded by an X-derived retrogene Ubl4b, which is specifically expressed in post-meiotic germ cells in mammals. As a germ cell-specific cytoplasmic protein, UBL4B is not present in somatic cells. Moreover, UBL4B is present in elongated spermatids, but not in spermatocytes and round spermatids, suggesting its function is restricted to late spermiogenesis. The function of UBL4A may be compensated by either UBL4B or other Ubl proteins in normal conditions. Both UBL4A and UBL4B contain a conserved Ubl domain with a beta-grasp Ubl fold, a common structure involved in protein-protein interactions.

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 637274141   11 VKTLDSQTRTFTVEEEITVKEFKEHIASSVNIPAEKQRLIYQGRVLQDDKKLKEYNVG-GKVIHLVER 77
Cdd:cd01807     5 VKILQGKECTIEVSPTESVLTVKQLVAEQLNVPVSQQRLVFKGKTLADEHSLSDYSIGpGSKIHLVVK 72

ubiquitin-like (Ubl) domain found in UV excision repair protein RAD23 homolog A (HR23A); HR23A, also termed RAD23A, is a DNA repair protein that binds to 19S subunit of the 26S proteasome and shuttles ubiquitinated proteins to the proteasome for degradation, which is required for efficient nucleotide excision repair (NER), a primary mechanism for removing UV-induced DNA lesions. HR23A also plays a critical role in the interaction of HIV-1 viral protein R (Vpr) with the proteasome, especially facilitating Vpr to promote protein poly-ubiquitination. HR23A contains an N-terminal ubiquitin-like (Ubl) domain that binds proteasomes and two C-terminal ubiquitin-associated (UBA) domains that bind ubiquitin or multi-ubiquitinated substrates. In addition, it has a XPC protein-binding domain that might be necessary for its efficient NER function.

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 637274141    7 LEVMVKTLDSQTRTFTVEEEITVKEFKEHIASSVN---IPAEKQRLIYQGRVLQDDKKLKEYNVGGK 70
Cdd:cd17126     1 VTITLKTLQQQTFKIRMEPDETVKVLKEKIEAEKGrdaFPVAGQKLIYAGKILSDDVPIRDYRIDEK 67

UV excision repair protein Rad23; All proteins in this family for which functions are known are components of a multiprotein complex used for targeting nucleotide excision repair to specific parts of the genome. In humans, Rad23 complexes with the XPC protein. This family is based on the phylogenomic analysis of JA Eisen (1999, Ph.D. Thesis, Stanford University). [DNA metabolism, DNA replication, recombination, and repair]

                           10        20        30        40        50        60        70
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 637274141     7 LEVMVKTLDSQTRTFTVEEEITVKEFKEHIASSV---NIPAEKQRLIYQGRVLQDDKKLKEYNV--GGKVIHLVER 77
Cdd:TIGR00601    1 MTLTFKTLQQQKFKIDMEPDETVKELKEKIEAEQgkdAYPVAQQKLIYSGKILSDDKTVKEYKIkeKDFVVVMVSK 76

ubiquitin-like (Ubl) domain 2 found in 2'-5'-oligoadenylate synthase-like protein (OASL) and similar proteins; OASL, also termed 2'-5'-OAS-related protein (2'-5'-OAS-RP), or 59 kDa 2'-5'-oligoadenylate synthase-like protein, or thyroid receptor-interacting protein 14, or TR-interacting protein 14 (TRIP-14), or p59 OASL (p59OASL), is an interferon (IFN)-induced antiviral protein that plays an important role in the IFNs-mediated antiviral signaling pathway. It inhibits respiratory syncytial virus replication and is targeted by the viral nonstructural protein 1 (NS1). It also displays antiviral activity against encephalomyocarditis virus (EMCV) and hepatitis C virus (HCV) via an alternative antiviral pathway independent of RNase L. Moreover, OASL does not have 2'-5'-OAS activity, but can bind double-stranded RNA (dsRNA) to enhance RIG-I signaling. OASL belongs to the 2'-5' oligoadenylate synthase (OAS) family. While each member of this family has a conserved N-terminal OAS catalytic domain, only OASL has two tandem C-terminal ubiquitin-like (Ubl) repeats, which are required for its antiviral activity. This family corresponds to the second Ubl domain.

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....*....
gi 637274141    9 VMVKTLDSQTRTFTVEEEITVKEFKEHIASSVNIPAEKQRLIYQGRVLQDDKKLKEYNV 67
Cdd:cd16103     4 IFVKFPDGTSKPYAINPEDTILDLKEKIEEQGGPPVEDQILLFQGQELRDKKSLKYYGI 62

Beta-grasp ubiquitin-like fold; Ubiquitin is a protein modifier that is involved in various cellular processes including transcriptional regulation, cell cycle control, and DNA repair in eukaryotes. The ubiquitination process comprises a cascade of E1, E2 and E3 enzymes that results in a covalent bond between the C-terminus of ubiquitin and the epsilon-amino group of a substrate lysine. Ubiquitin-like proteins have similar ubiquitin beta-grasp fold and attach to other proteins in a ubiquitin-like manner but with biochemically distinct roles. Ubiquitin and ubiquitin-like proteins conjugate and deconjugate via ligases and peptidases to covalently modify target polypeptides. Some other ubiquitin-like domains have adaptor roles in ubiquitin-signaling by mediating protein-protein interaction. In addition to Ubiquitin-like (Ubl) domain, Ras-associating (RA) domain, F0/F1 sub-domain of FERM (Four.1 protein, Ezrin, Radixin, Moesin) domain, TGS (ThrRS, GTPase and SpoT) domain, Ras-binding domain (RBD), Ubiquitin regulatory domain X (UBX), Dublecortin-like domain, and RING finger- and WD40-associated ubiquitin-like (RAWUL) domain have beta-grasp ubiquitin-like folds, and are included in this superfamily.

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 637274141    9 VMVKTLDSQTRTFTVEEEITVKEFKEHIASSVNIPAEKQRLIYQGRVLQDDKKLKEYN-VGGKVIHLV 75
Cdd:cd00196     1 VKVETPSLKKIVVAVPPSTTLRQVLEKVAKRIGLPPDVIRLLFNGQVLDDLMTAKQVGlEPGEELHFV 68

ubiquitin-like (Ubl) domain found in ubiquitin-like PHD and RING finger domain-containing proteins, UHRF1 and UHRF2, and similar proteins; 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, gastric cancer, esophageal squamous cell carcinoma, colorectal cancer, prostate cancer, and breast cancer. UHRF1 can 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 tumor suppressor pRB. It also plays a role in transcriptional repression of the cell cycle regulator p21. Moreover, UHRF1-dependent repression of 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) through interacting with 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        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|..
gi 637274141    9 VMVKTLDS--QTRTFTVEEEITVKEFKEHIASSVNIPAEKQRLIYQGRVLQDDKKLKEYNVG-GKVIHLVER 77
Cdd:cd01797     3 IQVRTMDGkkEARVDGLSKLTKIEDLRERIEEKFDVEPELQRLFYRGKQLEDGHTLFDYDVGlNDIIQLMVR 74

ubiquitin-like (Ubl) domain found in the eukaryotic Ddi1 family; The eukaryotic Ddi1 family, including yeast aspartyl protease DNA-damage inducible 1 (Ddi1) and Ddi1-like proteins from vertebrates and other eukaryotes, has been characterized by containing an N-terminal ubiquitin-like (Ubl) domain and a conserved retroviral aspartyl-protease-like domain (RVP) that is important in cell-cycle control. Yeast Ddi1 and many family members also contain a C-terminal ubiquitin-association (UBA) domain, however, Ddi1-like proteins from all vertebrates lack the UBA domain. Ddi1, also termed v-SNARE-master 1 (Vsm1), is an ubiquitin receptor involved in the cell cycle and late secretory pathway in Saccharomyces cerevisiae. It functions as an UBA-Ubl shuttle protein that is required for the proteasome to enable ubiquitin-dependent degradation of its ligands. For instance, Ddi1 plays an essential role in the final stages of proteasomal degradation of Ho endonuclease and of its cognate FBP, Ufo1. Moreover, Ddi1 and its associated protein Rad23p play a cooperative role as negative regulators in yeast PHO pathway. This family also includes mammalian regulatory solute carrier protein family 1 member 1 (RSC1A1), also termed transporter regulator RS1 (RS1), which mediates transcriptional and post-transcriptional regulation of Na(+)-D-glucose cotransporter SGLT1. Ddi1-like proteins play a significant role in cell cycle control, growth control, and trafficking in yeast and may play a crucial role in embryogenesis in higher eukaryotes.

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....*....
gi 637274141   13 TLDSQTRTFTVE--EEITVKEFKEHIASSVNIPAEKQRLIYQGRVLQDDKK-LKEYNVG 68
Cdd:cd01796     6 TTEDDDRLFSLEvsPDMTLEDLKALCEAETGIPAAEQVLLHNGQPLTDDKKtLEALGLK 64

ubiquitin-like (Ubl) domain found in ubiquitin-specific-processing protease 48 (USP48) and similar proteins; USP48, also termed USP31, or deubiquitinating enzyme 48, or ubiquitin thioesterase 48, or ubiquitin carboxyl-terminal hydrolase 48, belongs to the ubiquitin specific protease (USP) family that is one of at least seven deubiquitylating enzyme (DUB) families capable of deconjugating ubiquitin (Ub)and ubiquitin-like (Ubl) adducts. While the USP proteins have a conserved catalytic core domain, USP48 differs in its domain architecture. It contains an N-terminal USP domain, three DUSP (domain present in ubiquitin-specific protease) domains, and a C-terminal Ubl domain with a beta-grasp Ubl fold, a common structure involved in protein-protein interactions. USP48 is a deubiquitinating enzyme that interacts with TNF receptor-associated factor 2 (TRAF2) and has been implicated in activation of nuclear factor-kappaB (NF-kappaB). Moreover, as a nuclear deubiquitinase regulated by casein kinase 2 (CK2), USP48 controls the ubiquitin/proteasome-system (UPS)-dependent turnover of activated NF-kappaB/RelA in the nucleus together with the COP9 signalosome, suggesting a role of USP48 in a timely control of immune responses.

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|..
gi 637274141   21 FTVEEEITVKEFKEHIASSVNIPAEKQRLIYQGRVLQDDKK-LKEYNVG-GKVIHLVERAPP 80
Cdd:cd01795    10 LTVSSTTTLKELKLQIMEKFSVAPFDQHLYFNGRELTDDSAtLADLGILpGDVLYLKVDEPP 71

ubiquitin-like (Ubl) domain found in NEDD8 ultimate buster 1 (NUB1) and similar proteins; NUB1, also termed negative regulator of ubiquitin-like proteins 1, or renal carcinoma antigen NY-REN-18, or protein BS4, is a NEDD8-interacting protein that can be induced by interferon. It functions as a strong post-transcriptional down-regulator of the NEDD8 expression and plays critical roles in regulating many biological events, such as cell growth, NF-kappaB signaling, and biological responses to hypoxia. NUB1 can also interact with aryl hydrocarbon receptor-interacting protein-like 1 (AIPL1), which may function in the regulation of cell cycle progression. NUB1 contains a conserved ubiquitin-like (Ubl) domain with a beta-grasp Ubl fold, three ubiquitin-associated domains (UBA), a bipartite nuclear localization signal (NLS) and a PEST motif.

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|.
gi 637274141   27 ITVKEFKEHIASSVNIPAEKQRLIYQGRVLQDDKKLKEYNV--GGKVIHLV 75
Cdd:cd17062    27 ITGSELREKIAEELGVPEDRIKLISNGKVLKDEKTLAEQGVknNSQVMVLV 77

ubiquitin-like (Ubl) domain found in ubiquitin-like PHD and RING finger domain-containing protein 1(UHRF1); UHRF1, also termed inverted CCAAT box-binding protein of 90 kDa, or nuclear protein 95, or nuclear zinc finger protein Np95 (Np95), or RING finger protein 106, or transcription factor ICBP90, or E3 ubiquitin-protein ligase 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, gastric cancer, esophageal squamous cell carcinoma, colorectal cancer, prostate cancer, and breast cancer. UHRF1 can 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 tumor suppressor pRB. It also plays a role in transcriptional repression of the cell cycle regulator p21.Moreover, UHRF1-dependent repression of factors can facilitate the G1-S transition. It interacts with Tat-interacting protein of 60 kDa (TIP60) and induces degradation-independent ubiquitination ofTIP60. It is also an N-methylpurine DNA glycosylase (MPG)-interacting protein that binds MPG in a p53status-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. UHRF1 contains an N-terminal ubiquitin-like domain (Ubl), a tandem Tudor domain (TTD), a plant homeodomain (PHD) finger, a SET and RING finger associated (SRA) domain, and a C-terminal RING-finger domain. It specifically binds to hemimethylated DNA, double-stranded CpG dinucleotides, and recruits the maintenance methyltransferase DNMT1 to its hemimethylated DNA substrate through its SRA domain. UHRF1-dependent H3K23 ubiquitination has an essential role in maintenance DNA methylation and replication. The tandem Tudor domain directs UHRF1 binding to the heterochromatin mark histone H3K9me3 and the PHD finger targets UHRF1 to unmodified histone H3 in euchromatic regions. The RING-finger domain exhibits both autocatalytic E3 ubiquitin (Ub) ligase activity and activity against histone H3 and DNMT1.

                          10        20        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|..
gi 637274141    9 VMVKTLDS-QTRTFTVEEEIT-VKEFKEHIASSVNIPAEKQRLIYQGRVLQDDKKLKEYNVG-GKVIHLVER 77
Cdd:cd17122     3 IQVRTMDGkETHRIDSLSKLTkVEELRQKIQELFGVEPERQRLFYRGKQMEDGHTLFDYSVGlNDIVQLLVR 74

ubiquitin-like (Ubl) domain found in homocysteine-inducible endoplasmic reticulum stress protein HERP; HERP is an endoplasmic reticulum (ER) integral membrane protein containing an N-terminal ubiquitin-like (Ubl) domain with a beta-grasp Ubl fold. The Ubl domain is required for the degradation of HERP itself as well as for HERP-mediated anti-apoptotic effects. HERP is induced by the ER stress response pathway and is involved in improving the balance of folding capacity and protein loads in the ER. There are two types of HERP, HERP1 and HERP2, which are encoded by the HERPUD1 and HERPUD2 genes, respectively.

                          10        20        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 637274141    9 VMVKTLDSQTRTFTVEEEI--TVKEFKEHIASSV-NIPAEK-QRLIYQGRVLQDDKKLKEY-----NVGGKVIHLV 75
Cdd:cd01790     3 LVVKSPNQRIQDLTVNCTLgwTVLKLKEHLSEVYpSKPLPEdQKLIYSGKLLEDHQTLKDVlreddPEQVHTVHLV 78

ubiquitin-like (Ubl) domain found in BAG family molecular chaperone regulator 1 (BAG1) and similar proteins; BAG1, also termed Bcl-2-associated athanogene 1, or HAP, is a multifunctional protein involved in a variety of cellular functions such as apoptosis, transcription, and proliferative pathways, as well as in cell signaling and differentiation. It delivers chaperone-recognized unfolded substrates to the proteasome for degradation. BAG1 functions as a co-chaperone for Hsp70/Hsc70 to increase Hsp70 foldase activity. It also suppresses apoptosis and enhances neuronal differentiation. As an anti-apoptotic factor, BAG1 interacts with tau and regulates its proteasomal degradation. It also binds to BCR-ABL with a high affinity, and directly routes immature BCR-ABL for proteasomal degradation. It acts as a potential therapeutic target in Parkinson's disease. It also modulates huntingtin toxicity, aggregation, degradation, and subcellular distribution, suggesting a role in Huntington's disease. There are at least four isoforms of Bag1 protein that are formed by alternative initiation of translation within a common mRNA. BAG1 contains an N-terminal ubiquitin-like (Ubl) domain with a beta-grasp Ubl fold, and a C-terminal BAG domain.

                          10        20        30
                  ....*....|....*....|....*....|....*....
gi 637274141   24 EEEITVKEFKEHIASSVNIPAEKQRLIYQGRVLQDDKKL 62
Cdd:cd01812    21 EDEPTLQDLAEAIEEVTGVPVENQKLIFKGKSLKDPEQP 59

ubiquitin-like (Ubl) domain found in ubiquitin domain-containing protein UBFD1 and similar proteins; UBFD1, also termed ubiquitin-binding protein homolog (UBPH), is a polyubiquitin binding protein containing a conserved ubiquitin-like (Ubl) domain with a beta-grasp Ubl fold, a common structure involved in protein-protein interactions. It may play a role as nuclear factor-kappaB (NF-kappaB) regulator.

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....*.
gi 637274141   28 TVKEFKEHIASSVNIPAEKQRLIYQGrVLQDDKKLKEYNV--GGKV 71
Cdd:cd17047    21 TIAELKEHIETLTGVPPAMQKLMYKG-LLKDDKTLRELKVtkGAKV 65

EBNA-3B; Provisional

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 637274141  338 GAQTSSEGSTASQTS-PPAQPGTSTPPDAGRPTEGSPPAASSPGAAPTQTQGSQTGHPRvirishqtvepvvmmhmNIQD 416
Cdd:PHA03378  680 GANTMLPIQWAPGTMqPPPRAPTPMRPPAAPPGRAQRPAAATGRARPPAAAPGRARPPA-----------------AAPG 742

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 637274141  417 SSSPMGGSGTGGAPPAGTPGPIGHTPGMGGAPH-MPLPSLPPEFMQ--AVAHQITQQAMAAAASAAAGQQVPSFQSAPTR 493
Cdd:PHA03378  743 RARPPAAAPGRARPPAAAPGRARPPAAAPGAPTpQPPPQAPPAPQQrpRGAPTPQPPPQAGPTSMQLMPRAAPGQQGPTK 822

                         170       180       190       200       210       220       230
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 637274141  494 VMI-------ARPSAPSVRPTHPGSPQAPGQGPPSLGGNASLAQMISGLVGQLLMQPVIVAQGSGTTASAPSSVNTQA 564
Cdd:PHA03378  823 QILrqlltggVKRGRPSLKKPAALERQAAAGPTPSPGSGTSDKIVQAPVFYPPVLQPIQVMRQLGSVRAAAASTVTQA 900

ubiquitin-like (Ubl) domain found in non-canonical Inhibitor of kappa B kinases IKKepsilon and TBK1, and similar proteins; IKKepsilon and TBK1 (TRAF family member-associated NF-kappaB activator-binding kinase 1) are non-canonical members of IKK family. They have been characterized as activators of nuclear factor-kappaB (NF-kappaB), but they are not essential for NF-kappaB activation. They play critical roles in antiviral response via phosphorylation and activation of transcription factors IRF3, IRF7, STAT1 and STAT3. They are also involved in the survival, tumorigenesis and development of various cancers. Both IKKepsilon and TBK1 contain an N-terminal protein kinase domain followed a ubiquitin-like (Ubl) domain. The Ubl domain acts as a protein-protein interaction domain, and has been implicated in regulating kinase activity, which modulates interactions in the interferon pathway.

                          10        20        30
                  ....*....|....*....|....*....|....*
gi 637274141   28 TVKEFKEHIASSVNIPAEKQRLIYQGRVLQDDKKL 62
Cdd:cd12219    24 TLAEFQELIAEQTEIPAKNQLLLFEGQLLEEEVTL 58

large tegument protein UL36; Provisional

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 637274141  336 SRGAQTSSEGSTASQTSPPAQPGTSTPPDAGRPTEGSPPAASSPGAAPTQT------------------QGSQTGHPRVI 397
Cdd:PHA03247 2571 PRPAPRPSEPAVTSRARRPDAPPQSARPRAPVDDRGDPRGPAPPSPLPPDThapdppppspspaanepdPHPPPTVPPPE 2650

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 637274141  398 RISHQTVEPVVMMHMNIQDSSSPMGGSgtggAPPAGtPGPIGHTPGMGGAPHMPLPSLPPEFMQAVAHQITQQAMAAAAS 477
Cdd:PHA03247 2651 RPRDDPAPGRVSRPRRARRLGRAAQAS----SPPQR-PRRRAARPTVGSLTSLADPPPPPPTPEPAPHALVSATPLPPGP 2725

                         170       180       190       200       210       220       230       240
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 637274141  478 AAAGQQVPSFQSAPTrvmiarPSAPSVRPTHPGSPQAPGQGPPSLGGNASLAQMISGLVGQLLMQPVIVAQGSGTTASAP 557
Cdd:PHA03247 2726 AAARQASPALPAAPA------PPAVPAGPATPGGPARPARPPTTAGPPAPAPPAAPAAGPPRRLTRPAVASLSESRESLP 2799

                         250       260
                  ....*....|....*....|....
gi 637274141  558 SS---VNTQATFSTSNSASPPTAS 578
Cdd:PHA03247 2800 SPwdpADPPAAVLAPAAALPPAAS 2823

ubiquitin-like (Ubl) domain found in IQ and ubiquitin-like domain-containing protein (IQUB) and similar proteins; IQUB is an IQ motif and ubiquitin domain-containing protein that may play roles in cilia formation and/or maintenance. It contains a conserved ubiquitin-like (Ubl) domain with a beta-grasp Ubl fold, a common structure involved in protein-protein interactions.

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|.
gi 637274141   18 TRTFTVEEeiTVKEFKEHIASSVNIPAEKQRLIYQGRVLQDDKKLKEYNVG 68
Cdd:cd17061    17 TLAFTLGQ--TIGELKEHFSSELKIPPDVLQIMFDGKLVEDNTTLVDLGVR 65

ubiquitin-like (Ubl) domain found in ankyrin repeat domain-containing protein 60 (ANKRD60) and similar proteins; ANKRD60 is an uncharacterized ankyrin repeat domain-containing protein which also harbors a conserved ubiquitin-like (Ubl) domain with a beta-grasp Ubl fold, a common structure involved in protein-protein interactions.

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|..
gi 637274141   18 TRTFTVEE---EITVKEFKEHIASSVNIPAEKQRLIYQGRV-LQDDKKLKEYN-VGGKVIHL 74
Cdd:cd17063    13 EETFTVPNcypGMKVKELKSRLELVTGIPSHLQRLSYLDEGdLMDDSTLKYNDiVPGATITL 74

ubiquitin-like (Ubl) domain found in trans-2,3-enoyl-CoA reductase (TECR) and similar proteins; This family includes TECR and many TECR-like proteins, such as TECRL. TECR, also termed very-long-chain enoyl-CoA reductase, or synaptic glycoprotein SC2, or TER, or GPSN2, is a synaptic glycoprotein that catalyzes the fourth reaction in the synthesis of very long-chain fatty acids (VLCFA) which is the reduction step of the microsomal fatty acyl-elongation process. Diseases involving perturbations to normal synthesis and degradation of VLCFA (e.g. adrenoleukodystrophy and Zellweger syndrome) have significant neurological consequences. The mammalian TECR P182L mutation causes nonsyndromic mental retardation. Deletion of the yeast TECR (TSC13) homolog is lethal. TECR contains an N-terminal ubiquitin-like (Ubl) domain with a beta-grasp Ubl fold, a common structure involved in protein-protein interactions, as well as a C-terminal catalytic domain. TECRL, also termed steroid 5-alpha-reductase 2-like 2 protein (SRD5A2L2), is associated with life-threatening inherited arrhythmias displaying features of both long QT syndrome (LQTS) and catecholaminergic polymorphic ventricular tachycardia (CPVT). Both TECR and TECRL contain an N-terminal Ubl domain with a beta-grasp Ubl fold, and a C-terminal catalytic domain.

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....*..
gi 637274141   20 TFTVEEEITVKEFKEHIASSVNIP-AEKQRLIYQ---GRVLQDDKKLKEYNVGGKVI 72
Cdd:cd01801    15 TLEVSSSATVADLKKAIHKKKKKLyPERQRLRLEvpkGKVLKDDKTLSSYGVKDGST 71

DNA polymerase III subunit gamma/tau;

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 637274141  345 GSTASQTSPPAQPGTSTPPDAGRPTEGSPPAASSPGAAPTQTQGSQTGhprvirisHQTVEPVVmmhmniqdSSSPMGGS 424
Cdd:PRK07003  389 AAVGASAVPAVTAVTGAAGAALAPKAAAAAAATRAEAPPAAPAPPATA--------DRGDDAAD--------GDAPVPAK 452

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 637274141  425 GTGGAPPAGTPGPIGHTPGMGGAPHM-PLPSLPPefmqAVAHQITQQAMAAAASAAAGQQVPSFQSAPTRvmIARPSAPS 503
Cdd:PRK07003  453 ANARASADSRCDERDAQPPADSGSASaPASDAPP----DAAFEPAPRAAAPSAATPAAVPDARAPAAASR--EDAPAAAA 526

                         170       180
                  ....*....|....*....|....*.
gi 637274141  504 VRPTHPGSPQAPGQGPPSLGGNASLA 529
Cdd:PRK07003  527 PPAPEARPPTPAAAAPAARAGGAAAA 552