first ubiquitin-like (Ubl) domain located at the N-terminus of coronavirus SARS-CoV non-structural protein 3 (Nsp3) and related proteins; This ubiquitin-like (Ubl) domain (Ubl1) is found at the N-terminus of coronavirus Nsp3, a large multi-functional multi-domain protein which is an essential component of the replication/transcription complex (RTC). The functions of Ubl1 in CoVs are related to single-stranded RNA (ssRNA) binding and to interacting with the nucleocapsid (N) protein. SARS-CoV Ubl1 has been shown to bind ssRNA having AUA patterns, and since the 5'-UTR of the SARS-CoV genome has a number of AUA repeats, it may bind there. In mouse hepatitis virus (MHV), this Ubl1 domain binds the cognate N protein. Adjacent to Ubl1 is a Glu-rich acidic region (also referred to as hypervariable region, HVR); Ubl1 together with HVR has been called Nsp3a. Currently, the function of HVR in CoVs is unknown. This model corresponds to one of two Ubl domains in Nsp3; the other is located N-terminal to the papain-like protease (PLpro) and is not represented by this model.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 20336742  50 KEEIKEKVHKYNSAVTDKLKMTLNSNGIYTGFIKVQMELCKPAQPSPEPSSG-----------GCMNTLHISSTNTVGEV 118
Cdd:cd17219   1 KEEIKQKIQLYNLAVTDKLKMTLNSSGIYTGFIKVQMDLRRPITVRGGAAGNnnnetafylpkGSVNTLHISSTNTVREV 80

                        90       100       110       120       130       140
                ....*....|....*....|....*....|....*....|....*....|....*....|.
gi 20336742 119 IEALLRKFLVTESPTKFALYKRCHREDQVYACKLSDREHPLYLRLVAGPRTDTLSFVLREH 179
Cdd:cd17219  81 IEALLKKFLVADNPAKFALYKRCHKEDQVYACKLSDREHPLYLRLVAGPNTDTLSFVLREH 141

Ras-associating (RA) domain found in Ras-association domain-containing protein 3 (RASSF3); RASSF3 is a member of a family of six related classical RASSF1-6 proteins (the classical RASSF proteins). RASSF3 has three transcripts (A-C) due to alternative splicing of the exons. The RASSF3B and 3C isoforms are shorter than RASSF3A, and unlike RASSF3A do not contain the RA or SARAH domains. The RA domain of the classical RASSF proteins has a beta-grasp ubiquitin-like fold with low sequence similarity to ubiquitin. The RA domain mediates interactions with Ras and other small GTPases, and the SARAH domain mediates protein-protein interactions crucial in the pathways that induce cell cycle arrest and apoptosis. RASSF3A regulates apoptosis and cell cycle via p53 stabilization and possibly is involved in DNA repair.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 20336742  50 KEEIKEKVHKYNSAVTDKLKMTLNSNGIYTGFIKVQMELCKPAQPSPEPSSG-----------GCMNTLHISSTNTVGEV 118
Cdd:cd17219   1 KEEIKQKIQLYNLAVTDKLKMTLNSSGIYTGFIKVQMDLRRPITVRGGAAGNnnnetafylpkGSVNTLHISSTNTVREV 80

                        90       100       110       120       130       140
                ....*....|....*....|....*....|....*....|....*....|....*....|.
gi 20336742 119 IEALLRKFLVTESPTKFALYKRCHREDQVYACKLSDREHPLYLRLVAGPRTDTLSFVLREH 179
Cdd:cd17219  81 IEALLKKFLVADNPAKFALYKRCHKEDQVYACKLSDREHPLYLRLVAGPNTDTLSFVLREH 141

Ras association (RalGDS/AF-6) domain; RasGTP effectors (in cases of AF6, canoe and RalGDS); putative RasGTP effectors in other cases. Recent evidence (not yet in MEDLINE) shows that some RA domains do NOT bind RasGTP. Predicted structure similar to that determined, and that of the RasGTP-binding domain of Raf kinase.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 20336742    78 YTGFIKVQMELCKPAQPSpepssggcmNTLHISSTNTVGEVIEALLRKFLVTESPTKFALYKRCHREDQVYacKLSDREH 157
Cdd:pfam00788   1 DDGVLKVYTEDGKPGTTY---------KTILVSSSTTAEEVIEALLEKFGLEDDPRDYVLVEVLERGGGER--RLPDDEC 69

                          90       100
                  ....*....|....*....|...
gi 20336742   158 PLYLRLVAGPRTDTLSFVLREHE 180
Cdd:pfam00788  70 PLQIQLQWPRDASDSRFLLRKRD 92

Ras association (RalGDS/AF-6) domain; RasGTP effectors (in cases of AF6, canoe and RalGDS); putative RasGTP effectors in other cases. Kalhammer et al. have shown that not all RA domains bind RasGTP. Predicted structure similar to that determined, and that of the RasGTP-binding domain of Raf kinase. Predicted RA domains in PLC210 and nore1 found to bind RasGTP. Included outliers (Grb7, Grb14, adenylyl cyclases etc.)

                           10        20        30        40        50        60        70
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 20336742    106 TLHISSTNTVGEVIEALLRKFLVTESPTKFALYKR-CHREDQVyackLSDREHPLYLRLVAGPRTDTLSFVLREHE 180
Cdd:smart00314  19 TLRVSSRTTARDVIQQLLEKFHLTDDPEEYVLVEVlPDGKERV----LPDDENPLQLQKLWPRRGPNLRFVLRKRD 90

Ras-associating (RA) domain found in Ras-association domain-containing protein 3 (RASSF3); RASSF3 is a member of a family of six related classical RASSF1-6 proteins (the classical RASSF proteins). RASSF3 has three transcripts (A-C) due to alternative splicing of the exons. The RASSF3B and 3C isoforms are shorter than RASSF3A, and unlike RASSF3A do not contain the RA or SARAH domains. The RA domain of the classical RASSF proteins has a beta-grasp ubiquitin-like fold with low sequence similarity to ubiquitin. The RA domain mediates interactions with Ras and other small GTPases, and the SARAH domain mediates protein-protein interactions crucial in the pathways that induce cell cycle arrest and apoptosis. RASSF3A regulates apoptosis and cell cycle via p53 stabilization and possibly is involved in DNA repair.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 20336742  50 KEEIKEKVHKYNSAVTDKLKMTLNSNGIYTGFIKVQMELCKPAQPSPEPSSG-----------GCMNTLHISSTNTVGEV 118
Cdd:cd17219   1 KEEIKQKIQLYNLAVTDKLKMTLNSSGIYTGFIKVQMDLRRPITVRGGAAGNnnnetafylpkGSVNTLHISSTNTVREV 80

                        90       100       110       120       130       140
                ....*....|....*....|....*....|....*....|....*....|....*....|.
gi 20336742 119 IEALLRKFLVTESPTKFALYKRCHREDQVYACKLSDREHPLYLRLVAGPRTDTLSFVLREH 179
Cdd:cd17219  81 IEALLKKFLVADNPAKFALYKRCHKEDQVYACKLSDREHPLYLRLVAGPNTDTLSFVLREH 141

Ras-associating (RA) domain found in Ras-association domain family members, RASSF1, RASSF3, and RASSF5; The RASSF family of proteins shares a conserved RalGDS/AF6 Ras association (RA) domain which is located either at the C-terminus (RASSF1-6, the classical group) or at the N-terminus (RASSF7-10). RASSF1-6 contains a conserved SARAH (Salvador/RASSF/Hpo) motif adjacent to the RA domain that functions in scaffolding and regulatory interactions. The RA domain of the classical RASSF proteins has a beta-grasp ubiquitin-like fold with low sequence similarity to ubiquitin. Classical RASSF members interact either directly or indirectly with activated Ras. Ras proteins are small GTPases that are involved in cellular signal transduction. The classical RASSF proteins seem to modulate some of the growth inhibitory responses mediated by Ras and may serve as tumor suppressor genes. This family contains RASSF1, RASSF3, and RASSF5.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 20336742  76 GIYTGFIKVQMELCKPAQPSP------------EPSSG-------------GCMNTLHISSTNTVGEVIEALLRKFLVTE 130
Cdd:cd01778   1 GSFQGFIRVHMNLTRPISVSAgtrppsiydvlkLEDSGdsrktrtsfylpkDTVKALHITSDTTAREVIEALLKKFKITD 80

                        90       100       110       120       130
                ....*....|....*....|....*....|....*....|....*....|
gi 20336742 131 SPTKFALYKRCHRED-QVYACKLSDREHPLYLRLVAGPRTDTLSFVLREH 179
Cdd:cd01778  81 NPRKFALYERTHEEEgKVKLRKLSDDERPLYLCLLWGSQGDSKSFVLQEN 130

C-terminal SARAH domain found in Ras-association domain-containing protein 3 (RASSF3); RASSF3 is one of six related proteins, the classical RASSF proteins (RASSF1-6), that contain a conserved RalGDS/AF6 Ras association (RA) domain located towards the C-terminus. RASSF3 has three transcripts (A-C) due to alternative splicing of the exons. The RASSF3B and 3C isoforms are shorter than RASSF3A, and unlike RASSF3A do not contain the RA or SARAH (Salvador-RassF-Hippo) domains. RASSF3A regulates apoptosis and the cell cycle via p53 stabilization and is possibly involved in DNA repair. The RA domain of the classical RASSF proteins has a beta-grasp ubiquitin-like fold with low sequence similarity to ubiquitin. The RA domain mediates interactions with Ras and other small GTPases, and the SARAH domain mediates protein-protein interactions crucial in the pathways that induce cell cycle arrest and apoptosis. This model corresponds to the SARAH domain of RASSF3.

                        10        20        30        40
                ....*....|....*....|....*....|....*....|....*.
gi 20336742 183 EWEAFSLPELQNFLRILDKEEDEQLQSLKRRYTAYRQKLEEALGEV 228
Cdd:cd21891   1 MWEAFSLPELQNFLRILDKEEDEQLRSIKRRYNAYREKLEEALRGV 46

Ras association (RalGDS/AF-6) domain; RasGTP effectors (in cases of AF6, canoe and RalGDS); putative RasGTP effectors in other cases. Recent evidence (not yet in MEDLINE) shows that some RA domains do NOT bind RasGTP. Predicted structure similar to that determined, and that of the RasGTP-binding domain of Raf kinase.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 20336742    78 YTGFIKVQMELCKPAQPSpepssggcmNTLHISSTNTVGEVIEALLRKFLVTESPTKFALYKRCHREDQVYacKLSDREH 157
Cdd:pfam00788   1 DDGVLKVYTEDGKPGTTY---------KTILVSSSTTAEEVIEALLEKFGLEDDPRDYVLVEVLERGGGER--RLPDDEC 69

                          90       100
                  ....*....|....*....|...
gi 20336742   158 PLYLRLVAGPRTDTLSFVLREHE 180
Cdd:pfam00788  70 PLQIQLQWPRDASDSRFLLRKRD 92

Novel Ras effector 1 C-terminal SARAH (Sav/Rassf/Hpo) domain; The Nore1-SARAH, C-terminal, domain of Nore1, the tumour-suppressor, a novel Ras effector, has a characteriztic coiled-coil structure. It is a small helical module that is important in signal-transduction networks. The recombinant SARAH domain of Nore1 crystallizes as an anti-parallel homodimer with representative characteriztics of coiled coils. The central function of the SARAH domain seems to be the mediation of homo- and hetero-oligomerization between SARAH domain-containing proteins. Nore1 forms homo- and hetero complexes through its C-terminal SARAH (Sav/Rassf/Hpo) domain.

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|
gi 20336742   186 AFSLPELQNFLRILDKEEDEQLQSLKRRYTAYRQKLEEAL 225
Cdd:pfam16517   1 AFSLPELENFLRILDEEEEREIQQIRRKYTALRQKLQQAL 40

C-terminal SARAH domain found in scaffold protein salvador (Sav), Ras-association domain proteins, and mammalian STE20-like protein kinases (MST); The SARAH (Salvador-RassF-Hippo) domain family includes scaffold protein salvador (Sav), Ras-association domain proteins (RASSF1-6), and mammalian STE20-like protein kinase (MST) subfamily members (MST1-2 and Hippo). Sav is a scaffold protein mainly found in metazoans. Drosophila melanogaster Sav, also called Shar-pei (SHRP), promotes both cell cycle exit and apoptosis in Drosophila. It plays a key role in the Hippo/SWH (Sav/Wts/Hpo) signaling pathway. Human protein salvador homolog 1, also called 45 kDa WW domain protein (WW45), acts as a mammalian sterile 20-like kinase 1 (MST1)-binding protein required to enhance MST1-mediated apoptosis. It is a regulator of STK3/MST2 and STK4/MST1 in the Hippo signaling pathway. Classical RASSF proteins interact either directly or indirectly with activated Ras. Ras proteins are small GTPases that are involved in cellular signal transduction. They seem to modulate some of the growth inhibitory responses mediated by Ras and may serve as tumor suppressor genes. RASSF1-6 contains a conserved SARAH motif adjacent to the RA domain that functions in scaffolding and regulatory interactions. MST1/2 and Hippo are involved in a conserved pathway that governs cell contact inhibition, organ size control, and tumor development. MST1 and MST2 are STE20 family stress-activated, pro-apoptotic serine/threonine-protein kinases which, following caspase-cleavage, enter the nucleus and induces chromatin condensation followed by internucleosomal DNA fragmentation. They are key components of the Hippo signaling pathway which plays a pivotal role in organ size control and tumor suppression by restricting proliferation and promoting apoptosis. Hippo (Hpo), also called STE20-like kinase MST (dMST), is the Drosophila homolog of STE20-like protein kinases, MST1 and MST2. It is a STE20 family serine/threonine-protein kinase that functions as a tumor suppressor by restricting cell proliferation and promotes apoptosis in conjunction with salvador and warts. Hpo also plays a key role in the Hippo/SWH signaling pathway. This model corresponds to the C-terminal SARAH domain, a characteristic coiled-coil structure. It is a small helical module that is important in signal-transduction networks. The central function of the SARAH domain seems to be the mediation of homo- and heterodimerization between SARAH domain-containing proteins.

                        10        20        30        40
                ....*....|....*....|....*....|....*....|....*
gi 20336742 183 EWEAFSLPELQNFLRILDKEEDEQLQSLKRRYTAYRQKLEEALGE 227
Cdd:cd21883   1 QLKNFSLPELQMFLKMLDPEEEREIEQLVKKYTAYRQAILDALEE 45

Ras-associating (RA) domain, structurally similar to a beta-grasp ubiquitin-like fold; RA domain-containing proteins function by interacting with Ras proteins directly or indirectly and are involved in various functions ranging from tumor suppression to being oncoproteins. Ras proteins are small GTPases that are involved in cellular signal transduction. The RA domain has the beta-grasp ubiquitin-like (Ubl) fold with low sequence similarity to ubiquitin (Ub); Ub is a protein modifier in eukaryotes that is involved in various cellular processes, including transcriptional regulation, cell cycle control, and DNA repair. RA-containing proteins include RalGDS, AF6, RIN, RASSF1, SNX27, CYR1, STE50, and phospholipase C epsilon.

                        10        20        30        40        50        60        70
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|...
gi 20336742 106 TLHISSTNTVGEVIEALLRKFLVTESPTKFALYKRCHREDQVYacKLSDREHPLYLRLVAGPRTDTLSFVLRE 178
Cdd:cd17043  17 SILVSSTTTAREVVQLLLEKYGLEEDPEDYSLYEVSEKQETER--VLHDDECPLLIQLEWGPQGTEFRFVLKR 87

Ras-associating (RA) domain found in Ras-association domain-containing protein 6 (RASSF6); RASSF6 is a member of a family of six related classical RASSF1-6 proteins and is expressed as four transcripts via alternative splicing. All transcripts variant of RASSF6 contain the RA and SARAH domains. The RA domain of the classical RASSF protein family has the beta-grasp ubiquitin-like fold with low sequence similarity to ubiquitin. RA domains mediate interactions with Ras and other small GTPases, SARAH domains mediate protein-protein interactions crucial in the pathways that induce cell cycle arrest and apoptosis. RASSF6 is ubiquitiated and degraded by interacting with MDM2 to stabilize P53 and regulates apoptosis and cell cycle. RASSF6 is a tumor suppressor protein and is epigenetically silenced in childhood leukemia and neuroblastomas. Overexpression of RASSF6 causes apoptosis in HeLa cells.

                        10        20        30        40        50        60
                ....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 20336742 102 GCMNTLHISSTNTVGEVIEALLRKFLVTESPTKFALYKRCHREDQVyacKLSDREHPLYLRLVAGP 167
Cdd:cd17223  12 GSETKVRINSNMTTQEVIKQLLQKFKIENSPNEFALYIIHATGEKK---RLKNTDFPLWERLLQGP 74

Ras-associating (RA) domain found in Ras-association domain-containing protein 2 (RASSF2); RASSF2 is a member of a family of six related classical RASSF1-6 proteins. The RASSF2 gene is transcribed into two major isoforms (A and C). RASSF2 is structurally related to RASSF1A but unlike RASSF1A It is primarily a nuclear protein. RASSF2 contains the RA and SARAH domains. The RA domain of the classical RASSF protein family has the beta-grasp ubiquitin-like fold with low sequence similarity to ubiquitin. RA domains mediate interactions with Ras and other small GTPases, and SARAH domains mediate protein-protein interactions crucial in the pathways that induce cell cycle arrest and apoptosis. RASSF2 is inactivated in different cancers and cancer cell lines by promoter methylation and loss of expression, implicating the correlation and significance of RASSF2 in tumorigenesis. In addition to regulating apoptosis and proliferation RASSF2 may have other functions as RASSF2 knockout mice develop normally for the first two weeks but then develop growth retardation and die 4 weeks after birth.

                        10        20        30        40        50        60        70
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 20336742  98 PSSGGCMNtLHISSTNTVGEVIEALLRKFLVTESPTKFALYKRCHREDQVyacKLSDREHPLYLRLVAGP 167
Cdd:cd17221   9 PAYGSVTN-VRINSTMTTPQVLKLLLNKFKIENSAEEFALYIVHTSGEKQ---KLKATDYPLIARILQGP 74

C-terminal SARAH domain found in Ras-association domain-containing protein 2 (RASSF2); RASSF2 is one of six related proteins, the classical RASSF proteins (RASSF1-6), that contain a conserved RalGDS/AF6 Ras association (RA) domain located towards the C-terminus. It acts as a potential tumor suppressor that may promote apoptosis and cell cycle arrest. It is a KRAS-specific effector protein. It stabilizes STK3/MST2 by protecting it from proteasomal degradation. The RASSF2 gene is transcribed into two major isoforms (A and C). RASSF2 is structurally related to RASSF1A but unlike RASSF1A, it is primarily a nuclear protein. RASSF2 contains the RA and SARAH (Salvador-RassF-Hippo) domains. The RA domain of the classical RASSF proteins has a beta-grasp ubiquitin-like fold with low sequence similarity to ubiquitin. RA domains mediate interactions with Ras and other small GTPases, and SARAH domains mediate protein-protein interactions crucial in the pathways that induce cell cycle arrest and apoptosis. This model corresponds to the SARAH domain of RASSF2.

                        10        20        30        40
                ....*....|....*....|....*....|....*....|..
gi 20336742 187 FSLPELQNFLRILDKEEDEQLQSLKRRYTAYRQKLEEALGEV 228
Cdd:cd21893   5 FEMPVLKSFIQKLKEEEDREVKKLMRRYTVLRLMIEQRLQEI 46

FERM (Four.1 protein, Ezrin, Radixin, Moesin) domain, F1 sub-domain, found in pleckstrin homology domain-containing family H member 3 (PLEKHH3); PLEKHH3 is an uncharacterized Pleckstrin homology (PH) domain-containing protein that shows high sequence similarity with unconventional myosin-X, an actin-based motor protein that plays a critical role in diverse cellular motile events, such as filopodia formation/extension, phagocytosis, cell migration, and mitotic spindle maintenance, as well as a number of disease states including cancer metastasis and pathogen infection. In addition to two PH domains, PLEKHH3 harbors a MyTH4 domain, and a FERM (Band 4.1, ezrin, radixin, moesin) domain. The FERM domain is made up of three sub-domains, F1, F2, and F3. This family corresponds to the F1 sub-domain, which is also called the N-terminal ubiquitin-like structural domain of the FERM domain (FERM_N).

                        10        20        30        40
                ....*....|....*....|....*....|....*....|....*....
gi 20336742  98 PSSGGCmnTLHISSTNTVGEVIEALLRKFLVTESPTKFALYKRCHREDQ 146
Cdd:cd17207  11 PGAGAC--SIAITSHTTAEEVVRELVGRLGLSDSRNIFALYEQNGQEEQ 57