Domain present in Saccharomyces cerevisiae Shp1, Drosophila melanogaster eyes closed gene (eyc), and vertebrate p47;

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1281004807  224 EAITHTVTFWRNGFSVDDGPLLRLDDPENASFLESIRRSECPAELEPADRRTSVHVNLV-RREEDYPEPVKRRNaPFQGI 302
Cdd:smart00553   1 QKVIHTLTFWSNGFSVDDGPLRTYDDPENAEFLESIRRGEAPLELLRVAKGQPVNVDVEdHRDEDYVAPPGAFK-PFSGS 79

                           90
                   ....*....|....
gi 1281004807  303 GRTLASDSPNSVAP 316
Cdd:smart00553  80 GQKLGSPGPQSLST 93

UBA-like domain;

                          10        20        30
                  ....*....|....*....|....*....|....*..
gi 1281004807  21 INSFIEITSSSKEEALFFLESHNWDLDAAVSTFLDNH 57
Cdd:pfam14555   4 IAQFQAITGADEEVARQYLEAHNWDLEAAVNAFFDDG 40

Domain present in Saccharomyces cerevisiae Shp1, Drosophila melanogaster eyes closed gene (eyc), and vertebrate p47;

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1281004807  224 EAITHTVTFWRNGFSVDDGPLLRLDDPENASFLESIRRSECPAELEPADRRTSVHVNLV-RREEDYPEPVKRRNaPFQGI 302
Cdd:smart00553   1 QKVIHTLTFWSNGFSVDDGPLRTYDDPENAEFLESIRRGEAPLELLRVAKGQPVNVDVEdHRDEDYVAPPGAFK-PFSGS 79

                           90
                   ....*....|....
gi 1281004807  303 GRTLASDSPNSVAP 316
Cdd:smart00553  80 GQKLGSPGPQSLST 93

SEP domain; The SEP domain is named after Saccharomyces cerevisiae Shp1, Drosophila melanogaster eyes closed gene (eyc), and vertebrate p47. In p47, the SEP domain has been shown to bind to and inhibit the cysteine protease cathepsin L. Most SEP domains are succeeded closely by a UBX domain.

                          10        20        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 1281004807 230 VTFWRNGFSVDDGPLLRLDDPENASFLESIRRSECPAELEPADRRTSVHVNLV-RREEDYPEPvKRRNAPFQGIGR 304
Cdd:pfam08059   1 LTFWRNGFSVDDGPLRRYDDPANAEFLEAINRGEAPLELLNVAPGQGVDVNLEdRRDEDYVPP-KKKYKPFSGSGR 75

UBA-like domain;

                          10        20        30
                  ....*....|....*....|....*....|....*..
gi 1281004807  21 INSFIEITSSSKEEALFFLESHNWDLDAAVSTFLDNH 57
Cdd:pfam14555   4 IAQFQAITGADEEVARQYLEAHNWDLEAAVNAFFDDG 40

Domain present in ubiquitin-regulatory proteins; Present in FAF1 and Shp1p.

                           10        20        30        40        50        60        70
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 1281004807  344 TSLQLRLADGTRMVSRFNHHHTIRDIRGFIDASRPTGARNYQLQTMgFPPKQLAVLDQ---TIEQAGIANSVVIQK 416
Cdd:smart00166   2 CRLQIRLPDGSRLVRRFPSSDTLRTVYEFVSAALGDGNDPFTLNSP-FPRRTFTKDDYskkLLELALLPSSTLVLE 76

Domain present in Saccharomyces cerevisiae Shp1, Drosophila melanogaster eyes closed gene (eyc), and vertebrate p47;

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1281004807  224 EAITHTVTFWRNGFSVDDGPLLRLDDPENASFLESIRRSECPAELEPADRRTSVHVNLV-RREEDYPEPVKRRNaPFQGI 302
Cdd:smart00553   1 QKVIHTLTFWSNGFSVDDGPLRTYDDPENAEFLESIRRGEAPLELLRVAKGQPVNVDVEdHRDEDYVAPPGAFK-PFSGS 79

                           90
                   ....*....|....
gi 1281004807  303 GRTLASDSPNSVAP 316
Cdd:smart00553  80 GQKLGSPGPQSLST 93

SEP domain; The SEP domain is named after Saccharomyces cerevisiae Shp1, Drosophila melanogaster eyes closed gene (eyc), and vertebrate p47. In p47, the SEP domain has been shown to bind to and inhibit the cysteine protease cathepsin L. Most SEP domains are succeeded closely by a UBX domain.

                          10        20        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 1281004807 230 VTFWRNGFSVDDGPLLRLDDPENASFLESIRRSECPAELEPADRRTSVHVNLV-RREEDYPEPvKRRNAPFQGIGR 304
Cdd:pfam08059   1 LTFWRNGFSVDDGPLRRYDDPANAEFLEAINRGEAPLELLNVAPGQGVDVNLEdRRDEDYVPP-KKKYKPFSGSGR 75

Ubiquitin regulatory domain X (UBX) found in UBX domain protein 2B (UBXN2B) and similar proteins; UBXN2B, also termed NSFL1 cofactor p37, or p97 cofactor p37, belongs to the UBXD family of proteins that contains the ubiquitin regulatory domain X (UBX) with a beta-grasp ubiquitin-like fold, but without the C-terminal double glycine motif. UBX domain is typically located at the carboxyl terminus of proteins, and participates broadly in the regulation of protein degradation. UBXN2B is an adaptor protein of p97 (also known as VCP or Cdc48), which is a homohexameric AAA ATPase (ATPase associated with a variety of activities) involved in a variety of functions ranging from cell-cycle regulation to membrane fusion and protein degradation. UBXN2B forms a tight complex with p97 in the cytosol and localizes to the Golgi and endoplasmic reticulum (ER).

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1281004807 337 VDDSLPITSLQLRLADGTRMVSRFNHHHTIRDIRGFIDASRPTGARNYQLQTMGFPPKQLAVLDQTIEQAGIANSVVIQK 416
Cdd:cd17161     1 IDDSVPTTKIQIRLADGSRLIQRFNQSHRIHDIRQFIVQSRPVFAASDFLLVTTFPNKELTDESQTLQEADILNTVILQR 80

                  .
gi 1281004807 417 F 417
Cdd:cd17161    81 L 81

Ubiquitin regulatory domain X (UBX) found in UBX domain protein 2A (UBXN2A) and similar proteins; UBXN2A, also termed UBX domain-containing protein 4 (UBXD4), belongs to the UBXD family of proteins that contains the ubiquitin regulatory domain X (UBX) with a beta-grasp ubiquitin-like fold, but without the C-terminal double glycine motif. UBX domain is typically located at the carboxyl terminus of proteins, and participates broadly in the regulation of protein degradation. UBXN2A functions as a p97 (also known as VCP or Cdc48) adaptor protein facilitating the regulation of the cell surface number and stability of alpha3-containing neuronal nicotinic acetylcholine receptors (nAChRs). It also regulates nicotinic receptor degradation by modulating the E3 ligase activity of carboxyl terminus of Hsc70 interacting protein (CHIP) that is involved in the degradation of several disease-related proteins. In addition, UBXN2A is an important anticancer factor that contributes to p53 localization and activation as a host defense mechanism against cancerous growth. It acts as a potential mortalin inhibitor, as well as a potential chemotherapy sensitizer for clinical application. It binds to the oncoprotein mortalin-2 (mot-2), and further unsequesters p53 from mot-2 in the cytoplasm, resulting in translocation of p53 to the nucleus where p53 proteins activate their downstream biological effects, including apoptosis.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1281004807 337 VDDSLPITSLQLRLADGTRMVSRFNHHHTIRDIRGFIDASRPTGARNYQLQTMGFPPKQLAVLDQTIEQAGIANSVVIQK 416
Cdd:cd17160     1 LNELEPITNIQIWLADGRRIVQKFNLSHRISHVRDFVEKIQGSSMSVPFTLATSLPFRELLDETLTLQEADLQNAVIVQR 80

UBA-like domain found in uncharacterized protein C6orf106 and similar proteins; The family corresponds to a group of uncharacterized protein C6orf106 and its homologs mainly found in Metazoa. All family members contain a ubiquitin-associated (UBA)-like domain.

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|
gi 1281004807  17 NDAFINSFIEITSS-SKEEALFFLESHNWDLDAAVSTFLD 55
Cdd:cd14349     2 HEELISQFQSILGAqNESEAAFFLEMNNWNLQAAVGAYFD 41

UBA-like domain found in the NXF family of mRNA nuclear export factors and similar proteins; This family includes nuclear RNA export factors (NXF1/NXF2), FAS-associated factors (FAF1/2), tyrosyl-DNA phosphodiesterase 2 (TDP2), OTU domain-containing proteins (OTU7A/OTU7B), NSFL1 cofactor p47, defective in cullin neddylation protein 1 (DCN1)-like protein (DCNL1/DCNL2), yeast defective in cullin neddylation protein 1 (DCN1) and similar proteins. NXF proteins can stimulate nuclear export of mRNAs and facilitate the export of unspliced viral mRNA containing the constitutive transport element. FAF1 is an apoptotic signaling molecule that acts downstream in the Fas signal transduction pathway. It interacts with the cytoplasmic domain of Fas, but not to a Fas mutant that is deficient in signal transduction. FAF2 is the translation product of a highly expressed gene in the T-cells and eosinophils of atopic dermatitis patients compared with those of normal individuals. Its biological function remains unclear. TDP2 is a 5'-Tyr-DNA phosphodiesterase required for the efficient repair of topoisomerase II-induced DNA double strand breaks. OTU7A and OTU7B are zinc finger proteins that function as deubiquitinating enzymes. p47 is a major cofactor of the cytosolic AAA ATPase p97. It is required for the p97-regulated membrane reassembly of the endoplasmic reticulum (ER), the nuclear envelope and the Golgi apparatus. DCNL1 plays an essential role in the neddylation E3 complex and participates in the release of inhibitory effects of CAND1 on cullin-RING ligase E3 complex assembly and activity. The biological function of DCNL2 remains unclear. Yeast DCN1 is a scaffold-type E3 ligase for cullin neddylation. It can bind directly to cullins and the ubiquitin-like protein Nedd8-specific E2 (Ubc12), and regulate cullin neddylation and thus display ubiquitin ligase activity.

                          10        20        30
                  ....*....|....*....|....*....|.
gi 1281004807  24 FIEITSSSKEEALFFLESHNWDLDAAVSTFL 54
Cdd:cd14273     1 FMEITGADPETARQYLESNNWDLEAAINLYF 31

Domain present in ubiquitin-regulatory proteins; Present in FAF1 and Shp1p.

                           10        20        30        40        50        60        70
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 1281004807  344 TSLQLRLADGTRMVSRFNHHHTIRDIRGFIDASRPTGARNYQLQTMgFPPKQLAVLDQ---TIEQAGIANSVVIQK 416
Cdd:smart00166   2 CRLQIRLPDGSRLVRRFPSSDTLRTVYEFVSAALGDGNDPFTLNSP-FPRRTFTKDDYskkLLELALLPSSTLVLE 76

UBA-like domain found in yeast UBX domain-containing protein 1 (Ubx1) and similar proteins; Ubx1, also called suppressor of high-copy PP1 protein (Shp1), is the substrate-recruiting cofactor of AAA-adenosine triphosphatase Cdc48 in Saccharomyces cerevisiae. In concert with ubiquitin-like Atg8, Cdc48 and Ubx1 are involved in the regulation of autophagosome biogenesis. Ubx1 also functions as a regulator of phosphoprotein phosphatase 1 (PP1) with differential effects on glycogen metabolism, meiotic differentiation, and mitotic cell cycle progression. All family members contain an N-terminal ubiquitin-associated (UBA)-like domain.

                          10        20        30
                  ....*....|....*....|....*....|...
gi 1281004807  21 INSFIEITSSSKEEALFFLESHNWDLDAAVSTF 53
Cdd:cd14351     4 IQQFMELTGASPEVAQQYLEEYGGDLNDAINAY 36

UBA-like domain found in FAS-associated factor FAF1, FAF2 and similar proteins; FAF1, also called UBX domain-containing protein 12 or UBX domain-containing protein 3A, is an apoptotic signaling molecule that acts downstream in the Fas signal transduction pathway. It interacts with the cytoplasmic domain of Fas, but not to a Fas mutant that is deficient in signal transduction. FAF1 is widely expressed in adult and embryonic tissues, and in tumor cell lines, and is localized not only in the cytoplasm where it interacts with Fas, but also in the nucleus. FAF1 contains phosphorylation sites for protein kinase CK2 within the nuclear targeting domain. Phosphorylation influences nuclear localization of FAF1 but does not affect its potentiation of Fas-induced apoptosis. Other functions have also been attributed to FAF1. It inhibits nuclear factor-kappaB (NF-kappaB) by interfering with the nuclear translocation of the p65 subunit. Although the precise role of FAF1 in the ubiquitination pathway remains unclear, FAF1 interacts with valosin-containing protein (VCP) which is involved in the ubiquitin-proteosome pathway. FAF2, also called protein ETEA, UBX domain-containing protein 3B, or UBX domain-containing protein 8, is the translation product of a highly expressed gene in the T-cells and eosinophils of atopic dermatitis patients compared with those of normal individuals. FAF2 shows homology to Fas-associated factor 1 (FAF1). Both of them contain N-terminal ubiquitin-associated (UBA)-like domain, UAS and ubiquitin-like (UBX) domains. Compared to FAF1, however, FAF2 lacks the nuclear targeting domain. The function of FAF2 remains unclear. A yeast two-hybrid assay showed that it can interact with Fas. Because of its homology to FAF1, it is postulated that FAF2 could be involved in modulating Fas-mediated apoptosis of T-cells and eosinophils of atopic dermatitis patients, making them more resistant to apoptosis.

                          10        20        30
                  ....*....|....*....|....*....|..
gi 1281004807  24 FIEITS-SSKEEALFFLESHNWDLDAAVSTFL 54
Cdd:cd14353     1 FQSITGiEDSDQCRQILEAHNWDLEAAIQTAL 32

UBA-like domain found in DCN1-like protein DCNL1, DCNL2 and similar proteins; DCNL1 (defective in cullin neddylation protein 1-like protein 1), also called DCUN1 domain-containing protein 1, is encoded by squamous cell carcinoma-related oncogene SCCRO (DCUN1D1). It interacts with known cullin isoforms as well as ROC1, Ubc12 and CAND1, the components of the neddylation pathway. It plays an essential role in the neddylation E3 complex and participates in the release of inhibitory effects of CAND1 on cullin-RING ligase E3 complex assembly and activity. DCNL1 contains an N-terminal ubiquitin-associated (UBA)-like domain and a C-terminal cullin binding domain that binds to cullins and Rbx-1, components of an E3 ubiquitin ligase complex for neddylation. DCNL2 (defective in cullin neddylation protein 1-like protein 2), also called DCUN1 domain-containing protein 2, is encoded by gene DCUN1D2. Although its biological function remains unclear, DCNL2 shows high sequence similarity with DCNL1 and may also contribute to neddylation of cullin components of SCF-type E3 ubiquitin ligase complexes. Like DCNL1, DCNL2 contains an N-terminal UBA-like domain and a C-terminal cullin binding domain.

                          10        20        30
                  ....*....|....*....|....*....|...
gi 1281004807  24 FIEITSSSKEEALFFLESHNWDLDAAVSTFLDN 56
Cdd:cd14350     9 FMSITQANEKTAIQCLKDADWNLELAVDAYFQN 41

UBA-like domain found in Caenorhabditis elegans tyrosyl-DNA phosphodiesterase 2 (TDP2) and similar proteins; The family includes C. elegans TDP2 and its homologs found in bilateria. TDP2 (also known as TTRAP or EAPII) belongs to the Mg(2+)/Mn(2+)-dependent family of phosphodiesterases which contains an N-terminal ubiquitin-associated (UBA)-like domain and a C-terminal phosphodiesterase domain. It required for the efficient repair of topoisomerase II-induced DNA double strand breaks. The topoisomerase is covalently linked by a phosphotyrosyl bond to the 5'-terminus of the break. TDP2 cleaves the DNA 5'-phosphodiester bond and restores 5'-phosphate termini needed for subsequent DNA ligation and hence repair of the break. Tyrosyl-DNA phosphodiesterase 1 (TDP1), an enzyme that cleaves 3'-phosphotyrosyl bonds, and TDP2 are complementary activities; together, they allow cells to remove trapped topoisomerase from both 3'- and 5'-DNA termini. TDP2 has been reported as being involved in apoptosis, embryonic development, and transcriptional regulation.

                          10        20        30
                  ....*....|....*....|....*....|....*
gi 1281004807  21 INSFIEITSSSKEEALFFLESHNWDLDAAVSTFLD 55
Cdd:cd14672     3 CEEFAEITGTDEALAQFYLQDRDWDLEKALDVYFG 37

UBA domain-like superfamily; The ubiquitin-associated (UBA) domain-like superfamily contains alpha-helical structural homology ubiquitin-binding domains, including UBA domains and coupling of ubiquitin conjugation to endoplasmic reticulum degradation (CUE) domains which share a common three-helical bundle architecture. UBA domains are commonly occurring sequence motifs found in proteins involved in ubiquitin-mediated proteolysis. They contribute to ubiquitin (Ub) binding or ubiquitin-like (UbL) domain binding. However, some kinds of UBA domains can only bind the UbL domain, but not the Ub domain. UBA domains are normally comprised of compact three-helix bundles which contain a conserved GF/Y-loop. They can bind polyubiquitin with high affinity. They also bind monoubiquitin and other proteins. Most UBA domain-containing proteins have one UBA domain, but some harbor two or three UBA domains. CUE domain containing proteins are characterized by an FP and a di-leucine-like sequence and bind to monoubiquitin with varying affinities. Some higher eukaryotic CUE domain proteins do not bind monoubiquitin efficiently, since they carry LP, rather than FP among CUE domains. This superfamily also includes many UBA-like domains found in AMP-activated protein kinase (AMPK) related kinases, the NXF family of mRNA nuclear export factors, elongation factor Ts (EF-Ts), nascent polypeptide-associated complex subunit alpha (NACA) and similar proteins. Although many UBA-like domains may have a conserved TG but not GF/Y-loop, they still show a high level of structural and sequence similarity with three-helical ubiquitin binding domains.

                          10        20
                  ....*....|....*....|....*...
gi 1281004807  24 FIEITSSSKEEALFFLESHNWDLDAAVS 51
Cdd:cd00194     1 LVDITGASQEEAQQALEACGGNLNIAAN 28