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        60        70
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|...
gi 18859851   1 MKITVTT-SDDKVFCLDVAQDLELENLKALCAMEIGAEVSQIAVIFNGRELSSDKQTLQQCGVGDGDFIMLER 72
Cdd:cd01796   1 MKLTVTTeDDDRLFSLEVSPDMTLEDLKALCEAETGIPAAEQVLLHNGQPLTDDKKTLEALGLKDGDLLLLRP 73

UBA/TS-N domain; This small domain is composed of three alpha helices. This family includes the previously defined UBA and TS-N domains. The UBA-domain (ubiquitin associated domain) is a novel sequence motif found in several proteins having connections to ubiquitin and the ubiquitination pathway. The structure of the UBA domain consists of a compact three helix bundle. This domain is found at the N terminus of EF-TS hence the name TS-N. The structure of EF-TS is known and this domain is implicated in its interaction with EF-TU. The domain has been found in non EF-TS proteins such as alpha-NAC and MJ0280.

                          10        20        30
                  ....*....|....*....|....*....|....*
gi 18859851   411 EQDVTDLMALGYPRSDVLTVLRLCGGNKQAARSVL 445
Cdd:pfam00627   3 EEAIQRLVEMGFDREQVREALRATGNNVERAAEYL 37

Aspartyl protease; This family of eukaryotic aspartyl proteases have a fold similar to retroviral proteases which implies they function proteolytically during regulated protein turnover.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 18859851   217 QKNIQDNMAAAIEYNPEIFGTVTMLYINCKVNGIPVKAFVDSGAQTTIMSKDCAERCHVNRLIDTRWNGVAKGVGTQPIL 296
Cdd:pfam09668   1 QENIDENLEHAMEHHPEVFGRVTMLYINCEINGVPVKAFVDSGAQTSIMSPRCAERCGIMRLVDTRFAGIAKGVGTARIL 80

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|....
gi 18859851   297 GRIHMVQLQIENDHLTSSFTVLGQQPMDMLLGLDMLKRHQCLID 340
Cdd:pfam09668  81 GRIHMADVKIGGLFLPCSFSVIEGQDMDLLLGLDMLKRHQCCID 124

Ubiquitin family; This family contains a number of ubiquitin-like proteins: SUMO (smt3 homolog), Nedd8, Elongin B, Rub1, and Parkin. A number of them are thought to carry a distinctive five-residue motif termed the proteasome-interacting motif (PIM), which may have a biologically significant role in protein delivery to proteasomes and recruitment of proteasomes to transcription sites.

                          10        20        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|...
gi 18859851     3 ITVTTSDDKVFCLDVAQDLELENLKALCAMEIGAEVSQIAVIFNGRELsSDKQTLQQCGVGDGDFIMLERRRS 75
Cdd:pfam00240   1 ITVKTLDGKKITLEVDPTDTVLELKEKIAEKEGVPPEQQRLIYSGKVL-EDDQTLGEYGIEDGSTIHLVLRQR 72

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        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 18859851     1 MKITVTTSDDKVFCLDVAQDLELENLKALCAMEIGA---EVSQIAVIFNGRELSSDKqTLQQCGVGDGDFI--MLERRRS 75
Cdd:TIGR00601   1 MTLTFKTLQQQKFKIDMEPDETVKELKEKIEAEQGKdayPVAQQKLIYSGKILSDDK-TVKEYKIKEKDFVvvMVSKPKT 79

                          90       100       110
                  ....*....|....*....|....*....|..
gi 18859851    76 ANRPVGGNPAISTLdfsnIAVPGTSSGGSPPS 107
Cdd:TIGR00601  80 GTGKVAPPAATPTS----APTPTPSPPASPAS 107

UBA/TS-N domain; This small domain is composed of three alpha helices. This family includes the previously defined UBA and TS-N domains. The UBA-domain (ubiquitin associated domain) is a novel sequence motif found in several proteins having connections to ubiquitin and the ubiquitination pathway. The structure of the UBA domain consists of a compact three helix bundle. This domain is found at the N terminus of EF-TS hence the name TS-N. The structure of EF-TS is known and this domain is implicated in its interaction with EF-TU. The domain has been found in non EF-TS proteins such as alpha-NAC and MJ0280.

                          10        20        30
                  ....*....|....*....|....*....|....*
gi 18859851   411 EQDVTDLMALGYPRSDVLTVLRLCGGNKQAARSVL 445
Cdd:pfam00627   3 EEAIQRLVEMGFDREQVREALRATGNNVERAAEYL 37

UBA domain found in Saccharomyces cerevisiae DNA-damage response protein Ddi1 and similar proteins; Ddi1, also called v-SNARE-master 1 (Vsm1), is a ubiquitin receptor involved in regulation of the cell cycle and late secretory pathway in Saccharomyces cerevisiae. It functions as a ubiquitin association domain (UBA)- ubiquitin-like-domain (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. Ddi1 contains an N-terminal UBL domain and a C-terminal UBA domain. It also harbors a central retroviral aspartyl-protease-like domain (RVP) which may be important in cell-cycle control. At this point, Ddi1 may function proteolytically during regulated protein turnover in the cell. This family also includes mammalian regulatory solute carrier protein family 1 member 1 (RSC1A1), also called transporter regulator RS1 (RS1) which mediates transcriptional and post-transcriptional regulation of Na(+)-D-glucose cotransporter SGLT1.

                        10        20        30
                ....*....|....*....|....*....|....*.
gi 18859851 411 EQDVTDLMALGYPRSDVLTVLRLCGGNKQAARSVLL 446
Cdd:cd14309   1 EEKIAQLMDLGFSREEAIQALEATNGNVELAASLLF 36

Aspartyl protease; This family of eukaryotic aspartyl proteases have a fold similar to retroviral proteases which implies they function proteolytically during regulated protein turnover.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 18859851   217 QKNIQDNMAAAIEYNPEIFGTVTMLYINCKVNGIPVKAFVDSGAQTTIMSKDCAERCHVNRLIDTRWNGVAKGVGTQPIL 296
Cdd:pfam09668   1 QENIDENLEHAMEHHPEVFGRVTMLYINCEINGVPVKAFVDSGAQTSIMSPRCAERCGIMRLVDTRFAGIAKGVGTARIL 80

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|....
gi 18859851   297 GRIHMVQLQIENDHLTSSFTVLGQQPMDMLLGLDMLKRHQCLID 340
Cdd:pfam09668  81 GRIHMADVKIGGLFLPCSFSVIEGQDMDLLLGLDMLKRHQCCID 124

gag-polyprotein putative aspartyl protease; This family of putative aspartyl proteases is found pre-dominantly in retroviral proteins.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 18859851   243 INCKVNGIPVKAFVDSGAQTTIMSKDCAERCHVNRLIDTRWNGVAKGVGTQPIlGRIHMVQLQIENDHLTS-SFTVLGQQ 321
Cdd:pfam13975   1 VDVTINGRPVRFLVDTGASVTVISEALAERLGLDRLVDAYPVTVRTANGTVRA-ARVRLDSVKIGGIELRNvPAVVLPGD 79

                          90
                  ....*....|...
gi 18859851   322 PMDMLLGLDMLKR 334
Cdd:pfam13975  80 LDDVLLGMDFLKR 92

Retropepsins; pepsin-like aspartate proteases; The family includes pepsin-like aspartate proteases from retroviruses, retrotransposons and retroelements, as well as eukaryotic dna-damage-inducible proteins (DDIs), and bacterial aspartate peptidases. While fungal and mammalian pepsins are bilobal proteins with structurally related N and C-terminals, retropepsins are half as long as their fungal and mammalian counterparts. The monomers are structurally related to one lobe of the pepsin molecule and retropepsins function as homodimers. The active site aspartate occurs within a motif (Asp-Thr/Ser-Gly), as it does in pepsin. Retroviral aspartyl protease is synthesized as part of the POL polyprotein that contains an aspartyl protease, a reverse transcriptase, RNase H, and an integrase. The POL polyprotein undergoes specific enzymatic cleavage to yield the mature proteins. In aspartate peptidases, Asp residues are ligands of an activated water molecule in all examples where catalytic residues have been identified. This group of aspartate peptidases is classified by MEROPS as the peptidase family A2 (retropepsin family, clan AA), subfamily A2A.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 18859851 243 INCKVNGIPVKAFVDSGAQTTIMSKDCAERCHVNRLIDTRWNGVAKGVGTQ-PILGRIHMVQLQIENDHLTSSFTVLGQQ 321
Cdd:cd00303   1 LKGKINGVPVRALVDSGASVNFISESLAKKLGLPPRLLPTPLKVKGANGSSvKTLGVILPVTIGIGGKTFTVDFYVLDLL 80

                        90
                ....*....|..
gi 18859851 322 PMDMLLGLDMLK 333
Cdd:cd00303  81 SYDVILGRPWLE 92

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 18859851   3 ITVTTSDDKVFCLDVAQDLELENLKALCAMEIGAEVSQIAVIFNGRELsSDKQTLQQCGVGDGDFIML 70
Cdd:cd17039   1 ITVKTLDGKTYTVEVDPDDTVADLKEKIEEKTGIPVEQQRLIYNGKEL-KDDKTLSDYGIKDGSTIHL 67

ubiquitin-like (Ubl) domain found in Saccharomyces cerevisiae proteasome interacting protein Dsk2p and similar proteins; The family contains several fungal multiubiquitin receptors, including Saccharomyces cerevisiae Dsk2p and Schizosaccharomyces pombe Dph1p, both of which have been characterized as shuttle proteins transporting ubiquitinated substrates destined for degradation from the E3 ligase to the 26S proteasome. They interact with the proteasome through their N-terminal ubiquitin-like domain (Ubl) and with ubiquitin (Ub) through their C-terminal Ub-associated domain (UBA). S. cerevisiae Dsk2p is a nuclear-enriched protein that may involve in the ubiquitin-proteasome proteolytic pathway through interacting with K48-linked polyubiquitin and the proteasome. Moreover, it has been implicated in spindle pole duplication through assisting in Cdc31 assembly into the new spindle pole body (SPB). S. pombe Dph1p is an ubiquitin (Ub0 receptor working in concert with the class V myosin, Myo52, to target the degradation of the S. pombe CLIP-170 homolog, Tip1. It also can protect Ub chains against disassembly by deubiquitinating enzymes.

                        10        20        30        40        50        60        70
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....
gi 18859851   1 MKITVTTSDDKVFCLDVAQDLELENLKALCAMEIGAEVSQIAVIFNGRELsSDKQTLQQCGVGDGDFIMLERRR 74
Cdd:cd16106   1 IKVTVKCSNGKKFTVEVEPDATVLELKELIAEKSDIPAEQQRLIYKGKIL-KDEETLSSYKIQDGHTVHLVKGA 73

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 18859851   1 MKITVTTSDDKVFCLDVAQDLELENLKALCAMEIGA-EVSQIAVIFNGRELsSDKQTLQQCGVGDGDFI 68
Cdd:cd01805   1 MKITFKTLQQQTFEIEVEPSDTVLELKEKIEQEQGDfPASGQKLIYSGKVL-KDDKTLSEYNIKEKDFV 68

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 18859851  45 FNGRELSSDKQTLQQCGVGDGDFIMLErrrsANRPVGGNPAISTLDFSNIAVPGTSSGGS 104
Cdd:cd01795  40 FNGRELTDDSATLADLGILPGDVLYLK----VDEPPDDPDDADEADVSRARVPEEGFKGT 95

Predicted aspartyl protease [General function prediction only];

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 18859851 242 YINCKVNGIPVKAFVDSGAQTTIMSKDCAERCHVNRLIDTRW------NGVAKGVgtqpiLGRIHMVQL-QIENDHLTss 314
Cdd:COG3577  43 VVEGTINGQPVRFLVDTGASTVVLSESDARRLGLDPEDLGRPvrvqtaNGVVRAA-----RVRLDSVRIgGITLRNVR-- 115

                        90       100
                ....*....|....*....|...
gi 18859851 315 FTVL-GQQPMDMLLGLDMLKRHQ 336
Cdd:COG3577 116 AVVLpGGELDDGLLGMSFLGRLD 138

NRIP_C; putative nuclear receptor interacting protein; Proteins in this family have been described as probable nuclear receptor interacting proteins. The C-terminal domain of this family is homologous to the retroviral aspartyl protease domain. The domain is structurally related to one lobe of the pepsin molecule. The conserved active site aspartate occurs within a motif (Asp-Thr/Ser-Gly), as it does in pepsin. Asp residues are ligands of an activated water molecule in all examples where catalytic residues have been identified. This group of aspartate peptidases is classified by MEROPS as the peptidase family A2 (retropepsin family, clan AA), subfamily A2A.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 18859851 243 INCKVNGIPVKAFVDSGAQTTIMSKDCAERCHV-NRLIDTRWNGVAKGVGTQ-PILGRIHMVQLQIENDHLTSSFTVLGQ 320
Cdd:cd05480   1 VSCQCAGKELRALVDTGCQYNLISAACLDRLGLkERVLKAKAEEEAPSLPTSvKVIGQIERLVLQLGQLTVECSAQVVDD 80

                        90       100
                ....*....|....*....|...
gi 18859851 321 QPMDMLLGLDMLKRHQCLIDLQR 343
Cdd:cd05480  81 NEKNFSLGLQTLKSLKCVINLEK 103

Bacterial aspartate proteases, retropepsin-like protease family; This family of bacteria aspartate proteases is a subfamily of retropepsin-like protease family, which includes enzymes from retrovirus and retrotransposons. While fungal and mammalian pepsin-like aspartate proteases are bilobal proteins with structurally related N- and C-termini, this family of bacteria aspartate proteases is half as long as their fungal and mammalian counterparts. The monomers are structurally related to one lobe of the pepsin molecule and function as homodimers. The active site aspartate occurs within a motif (Asp-Thr/Ser-Gly), as it does in pepsin. In aspartate peptidases, Asp residues are ligands of an activated water molecule in all examples where catalytic residues have been identified. This group of aspartate proteases is classified by MEROPS as the peptidase family A2 (retropepsin family, clan AA), subfamily A2A.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 18859851 240 MLYINCKVNGIPVKAFVDSGAQTTIMSKDCAERCHVN-RLIDTRWNGVAKGVgTQPILGRIHMVQL-QIENDHLTSSFTV 317
Cdd:cd05483   2 HFVVPVTINGQPVRFLLDTGASTTVISEELAERLGLPlTLGGKVTVQTANGR-VRAARVRLDSLQIgGITLRNVPAVVLP 80

                        90
                ....*....|....*.
gi 18859851 318 LGQQPMDMLLGLDMLK 333
Cdd:cd05483  81 GDALGVDGLLGMDFLR 96

ubiquitin-like (Ubl) domain found in transmembrane and ubiquitin-like domain-containing proteins TMUB1, TMUB2, and similar proteins; TMUB1, also termed dendritic cell-derived ubiquitin-like protein (DULP), or hepatocyte odd protein shuttling protein, or ubiquitin-like protein SB144, or HOPS, is highly expressed in the nervous system. It is involved in the termination of liver regeneration and plays a negative role in interleukin-6-induced hepatocyte proliferation. The overexpression of Tmub1 has been shown to play a role in the inhibition of cell proliferation. TMUB1 has been implicated in the regulation of locomotor activity and wakefulness in mice, perhaps acting through its interaction with CAMLG. It also facilitates the recycling of AMPA receptors into synaptic membrane in cultured primary neurons. TMUB1 contains transmembrane domains and a ubiquitin-like (Ubl) domain with a beta-grasp Ubl fold. TMUB2 is an uncharacterized transmembrane domain and Ubl domain-containing protein that shows high sequence similarity to TMUB1.

                        10        20        30
                ....*....|....*....|....*....|...
gi 18859851  36 AEVSQIAVIFNGRELSSDKQTLQQCGVGDGDFI 68
Cdd:cd17057  37 AQGKRVRLIYQGQLLRDDSRTLSSYGIQDGSVI 69

Retroviral aspartyl protease; Single domain aspartyl proteases from retroviruses, retrotransposons, and badnaviruses (plant dsDNA viruses). These proteases are generally part of a larger polyprotein; usually pol, more rarely gag. Retroviral proteases appear to be homologous to a single domain of the two-domain eukaryotic aspartyl proteases.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 18859851   244 NCKVNGIPVKAFVDSGAQTTIMSKDCA-------ERCHVNRLIDTRWNGVAKGVGTQPilgrihMVQLQIENDHLTSSFT 316
Cdd:pfam08284  23 TFLVNSIPATVLFDSGATHSFISHAFVgklklpvESLSNPLCIETPTGGSVTTNLICP------SCPIEIQGISFLADLI 96

                          90       100
                  ....*....|....*....|....*..
gi 18859851   317 VLGQQPMDMLLGLDMLKRHQCLIDLQR 343
Cdd:pfam08284  97 LLDMKDLDVILGMDWLSKNKANIDCAR 123