Ras-associating (RA) domain found in Ras-association domain-containing protein 4 (RASSF4); RASSF4 is a member of a family of six related classical RASSF1-6 proteins and is broadly expressed in normal tissues. RASSF4 expression is reduced in tumor cell lines and primary tumors by promoter specific hypermethylation. RASSF4 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. RASSF4 inhibits lung cancer cell proliferation and invasion.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 432106035 228 NHKTSVFTPAYGSVTNVRVNSTMTTLQVLSLLLSKFRVENGPSEFALYVVHESGERTKLKDCEYPLISRVLHGPSEKIAR 307
Cdd:cd17222    1 NHKTSVFTPAYGSVTNVRVNSTMTTPQVLKLLLNKFRVENSPDEFALYLVHESGERTKLKDTEYPLISRILHGPCEKIAR 80

                 ....*..
gi 432106035 308 IFLMEAD 314
Cdd:cd17222   81 IFLMETD 87

Ras-associating (RA) domain found in Ras-association domain-containing protein 4 (RASSF4); RASSF4 is a member of a family of six related classical RASSF1-6 proteins and is broadly expressed in normal tissues. RASSF4 expression is reduced in tumor cell lines and primary tumors by promoter specific hypermethylation. RASSF4 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. RASSF4 inhibits lung cancer cell proliferation and invasion.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 432106035 228 NHKTSVFTPAYGSVTNVRVNSTMTTLQVLSLLLSKFRVENGPSEFALYVVHESGERTKLKDCEYPLISRVLHGPSEKIAR 307
Cdd:cd17222    1 NHKTSVFTPAYGSVTNVRVNSTMTTPQVLKLLLNKFRVENSPDEFALYLVHESGERTKLKDTEYPLISRILHGPCEKIAR 80

                 ....*..
gi 432106035 308 IFLMEAD 314
Cdd:cd17222   81 IFLMETD 87

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        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 432106035   225 HFYNHKTSVFTPAYGSVTNVRVNSTMTTLQVLSLLLSKFRVENGPSEFALYVVHESGERTKLKDCEYPLISRVLHGPSEK 304
Cdd:smart00314   1 DTFVLRVYVDDLPGGTYKTLRVSSRTTARDVIQQLLEKFHLTDDPEEYVLVEVLPDGKERVLPDDENPLQLQKLWPRRGP 80

                           90
                   ....*....|
gi 432106035   305 IARIFLMEAD 314
Cdd:smart00314  81 NLRFVLRKRD 90

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 432106035  328 KFEMPVLDSFIEKLKEEEQREIIKLTMKFQALRLTMLQRL 367
Cdd:pfam16517   1 AFSLPELENFLRILDEEEEREIQQIRRKYTALRQKLQQAL 40

Ras-associating (RA) domain found in Ras-association domain-containing protein 4 (RASSF4); RASSF4 is a member of a family of six related classical RASSF1-6 proteins and is broadly expressed in normal tissues. RASSF4 expression is reduced in tumor cell lines and primary tumors by promoter specific hypermethylation. RASSF4 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. RASSF4 inhibits lung cancer cell proliferation and invasion.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 432106035 228 NHKTSVFTPAYGSVTNVRVNSTMTTLQVLSLLLSKFRVENGPSEFALYVVHESGERTKLKDCEYPLISRVLHGPSEKIAR 307
Cdd:cd17222    1 NHKTSVFTPAYGSVTNVRVNSTMTTPQVLKLLLNKFRVENSPDEFALYLVHESGERTKLKDTEYPLISRILHGPCEKIAR 80

                 ....*..
gi 432106035 308 IFLMEAD 314
Cdd:cd17222   81 IFLMETD 87

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        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 432106035 228 NHKTSVFTPAYGSVTNVRVNSTMTTLQVLSLLLSKFRVENGPSEFALYVVHESGERTKLKDCEYPLISRVLHGPSEKIAR 307
Cdd:cd17221    1 NHKTSVFTPAYGSVTNVRINSTMTTPQVLKLLLNKFKIENSAEEFALYIVHTSGEKQKLKATDYPLIARILQGPCEQVSK 80

                 ....*..
gi 432106035 308 IFLMEAD 314
Cdd:cd17221   81 VFLMEKD 87

C-terminal SARAH domain found in Ras-association domain-containing protein 4 (RASSF4); RASSF4 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 also functions as a KRAS effector protein. RASSF4 is broadly expressed in normal tissues. Its expression is reduced in tumor cell lines and primary tumors by promoter specific hypermethylation. RASSF4 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 RASSF4.

                         10        20        30        40
                 ....*....|....*....|....*....|....*....|....*.
gi 432106035 325 QYIKFEMPVLDSFIEKLKEEEQREIIKLTMKFQALRLTMLQRLEQL 370
Cdd:cd21894    1 QYIKFEMPVLDSFVEKLKEEEEREIIKLTRKYSALRSMILQQLEQL 46

C-terminal SARAH domain found in Ras-association domain proteins, RASSF2, RASSF4, and RASSF6; The RASSF subfamily 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). The classical RASSF proteins seem to modulate some of the growth inhibitory responses mediated by Ras and may serve as tumor suppressor genes. They interact either directly or indirectly with activated Ras. Ras proteins are small GTPases that are involved in cellular signal transduction. RASSF1-6 contain a conserved C-terminal SARAH (Salvador-RassF-Hippo) 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. This model corresponds to the SARAH domain of RASSF2, RASSF4, and RASSF6. It is a characteristic coiled-coil structure that is important in signal-transduction networks. The central function of the SARAH domain is the mediation of homo- and heterodimerization between SARAH domain-containing proteins.

                         10        20        30        40
                 ....*....|....*....|....*....|....*....|....*
gi 432106035 325 QYIKFEMPVLDSFIEKLKEEEQREIIKLTMKFQALRLTMLQRLEQ 369
Cdd:cd21886    1 QYLNFSMPELRAFLRKFQEEEEREVEKIKEKYEELKRRIKKRMEE 45

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 432106035  227 YNHKTSVFTPAYGSVT---NVRVNSTMTTLQVLSLLLSKFRVENGPSEFALYVV--HESGERtKLKDCEYPLISRVLHGP 301
Cdd:pfam00788   1 DDGVLKVYTEDGKPGTtykTILVSSSTTAEEVIEALLEKFGLEDDPRDYVLVEVleRGGGER-RLPDDECPLQIQLQWPR 79

                          90
                  ....*....|.
gi 432106035  302 SEKIARIFLME 312
Cdd:pfam00788  80 DASDSRFLLRK 90

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 432106035 238 YGSVTNVRVNSTMTTLQVLSLLLSKFRVENGPSEFALYVVHESG--ERtKLKDCEYPLISRVLHGPSEKIARIFLME 312
Cdd:cd17043   12 GSAYKSILVSSTTTAREVVQLLLEKYGLEEDPEDYSLYEVSEKQetER-VLHDDECPLLIQLEWGPQGTEFRFVLKR 87

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 432106035 325 QYIKFEMPVLDSFIEKLKEEEQREIIKLTMKFQALRLTMLQRLE 368
Cdd:cd21883    1 QLKNFSLPELQMFLKMLDPEEEREIEQLVKKYTAYRQAILDALE 44

Ras-associating (RA) domain 1 found in Afadin; Afadin, also termed ALL1-fused gene from chromosome 6 protein (AF-6), or canoe, is involved in many fundamental signaling cascades in cells. In addition, it is involved in oncogenesis and metastasis. Afadin has multiple domains: from the N-terminus to the C-terminus it has two Ras-associated (RA) domains, a forkhead-associated domain, a dilute domain, a PDZ domain, three proline-rich domains, and an F-actin-binding domain. RA domain-containing proteins function by interacting with Ras proteins directly or indirectly and are involved in several different functions ranging from tumor suppression to being oncoproteins. Ras proteins are small GTPases that are involved in cellular signal transduction. The RA domain has a 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 in eukaryotes. Afadin is abundant at cadherin-based adherens junctions in epithelial cells, endothelial cells, and fibroblasts. This family corresponds to the first RA domain of afadin, which mediates its self-association.

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|....
gi 432106035 244 VRVNSTMTTLQVLSLLLSKFRVEN---GPSEFALYVVHESGERTKLKDCEYPLI 294
Cdd:cd01782   40 IRVSSTATTQDVIETLIEKFRPDMrmlSNPRYSLYEVHPNGEERKLDDDEKPLV 93

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 432106035 230 KTSVFTPAyGSVTNVRVNSTMTTLQVLSLLLSKFRVENGPSEFALY--VVHESGERT--KLKDCEYPLISRVLHGPSEKI 305
Cdd:cd01778   44 RTSFYLPK-DTVKALHITSDTTAREVIEALLKKFKITDNPRKFALYerTHEEEGKVKlrKLSDDERPLYLCLLWGSQGDS 122

                 ....*..
gi 432106035 306 ARIFLME 312
Cdd:cd01778  123 KSFVLQE 129

Ras-associating (RA) domain of Ras and Rab interactor (Rin) protein family; Family of Ras-interaction/interference (Rin) proteins, also known as Ras and Rab interactors, is composed of Rin1, Rin2, and Rin3, which have multifunctional domains, including SH2 and proline-rich domains in the N-terminal region, and RH, VPS9, and RA domains in the C-terminal region. RA domain-containing proteins function by interacting with Ras proteins directly or indirectly and are involved in several different 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; ubiquitin is a protein modifier in eukaryotes that is involved in various cellular processes including transcriptional regulation, cell cycle control, and DNA repair. The RA domains of Rin1, Rin2, and Rin3 are well conserved and they all have Ras binding characteristics.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 432106035 230 KTSVFTPAYGSVT--NVRVNSTMTTLQVLSLLLSKFRVENgPSEFALYVVHEsGERTKLKDCEYP-LISRVLHGPSEKIA 306
Cdd:cd01776    5 RVAVPDENNGSIVskTLPVRPSMTAREVCKMIAHKFRVTN-PQDYGLFLLVD-GEEIQLEDNECPqLIKGELLATSKKPC 82

                 ..
gi 432106035 307 RI 308
Cdd:cd01776   83 YF 84