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 847141584 164 NHKTSVFTPAYGSVTNVRVTSKMNTCQVLKLLLWKFRVENSPNEFALYLLHESGERTKLGETEFPLICRILQGPSERIAK 243
Cdd:cd17222    1 NHKTSVFTPAYGSVTNVRVNSTMTTPQVLKLLLNKFRVENSPDEFALYLVHESGERTKLKDTEYPLISRILHGPCEKIAR 80

                 ....*..
gi 847141584 244 IFMMETD 250
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 847141584 164 NHKTSVFTPAYGSVTNVRVTSKMNTCQVLKLLLWKFRVENSPNEFALYLLHESGERTKLGETEFPLICRILQGPSERIAK 243
Cdd:cd17222    1 NHKTSVFTPAYGSVTNVRVNSTMTTPQVLKLLLNKFRVENSPDEFALYLVHESGERTKLKDTEYPLISRILHGPCEKIAR 80

                 ....*..
gi 847141584 244 IFMMETD 250
Cdd:cd17222   81 IFLMETD 87

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 847141584  264 KFEMPVLDSFVKKLKEEEDREIIKLTEKYNALRMMMVQRL 303
Cdd:pfam16517   1 AFSLPELENFLRILDEEEEREIQQIRRKYTALRQKLQQAL 40

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 847141584  163 YNHKTSVFTPAYGSVT---NVRVTSKMNTCQVLKLLLWKFRVENSPNEFAL--YLLHESGERtKLGETEFPLICRILQGP 237
Cdd:pfam00788   1 DDGVLKVYTEDGKPGTtykTILVSSSTTAEEVIEALLEKFGLEDDPRDYVLveVLERGGGER-RLPDDECPLQIQLQWPR 79

                          90
                  ....*....|...
gi 847141584  238 SERIAKIFMMETD 250
Cdd:pfam00788  80 DASDSRFLLRKRD 92

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 847141584 164 NHKTSVFTPAYGSVTNVRVTSKMNTCQVLKLLLWKFRVENSPNEFALYLLHESGERTKLGETEFPLICRILQGPSERIAK 243
Cdd:cd17222    1 NHKTSVFTPAYGSVTNVRVNSTMTTPQVLKLLLNKFRVENSPDEFALYLVHESGERTKLKDTEYPLISRILHGPCEKIAR 80

                 ....*..
gi 847141584 244 IFMMETD 250
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 847141584 164 NHKTSVFTPAYGSVTNVRVTSKMNTCQVLKLLLWKFRVENSPNEFALYLLHESGERTKLGETEFPLICRILQGPSERIAK 243
Cdd:cd17221    1 NHKTSVFTPAYGSVTNVRINSTMTTPQVLKLLLNKFKIENSAEEFALYIVHTSGEKQKLKATDYPLIARILQGPCEQVSK 80

                 ....*..
gi 847141584 244 IFMMETD 250
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 847141584 261 QYIKFEMPVLDSFVKKLKEEEDREIIKLTEKYNALRMMMVQRLEQL 306
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 847141584 261 QYIKFEMPVLDSFVKKLKEEEDREIIKLTEKYNALRMMMVQRLEQ 305
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. 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 847141584   161 HFYNHKTSVFTPAYGSVTNVRVTSKMNTCQVLKLLLWKFRVENSPNEFALYLLHESGERTKLGETEFPLICRILQGPSER 240
Cdd:smart00314   1 DTFVLRVYVDDLPGGTYKTLRVSSRTTARDVIQQLLEKFHLTDDPEEYVLVEVLPDGKERVLPDDENPLQLQKLWPRRGP 80

                           90
                   ....*....|
gi 847141584   241 IAKIFMMETD 250
Cdd:smart00314  81 NLRFVLRKRD 90

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 847141584 261 QYIKFEMPVLDSFVKKLKEEEDREIIKLTEKYNALRMMMVQRLE 304
Cdd:cd21883    1 QLKNFSLPELQMFLKMLDPEEEREIEQLVKKYTAYRQAILDALE 44

Ras-associating (RA) domain of Ras-association domain family 5 (RASSF5); RASSF5, also called New ras effector 1 (NORE1), or regulator for cell adhesion and polarization enriched in lymphoid tissues (RAPL), is a member of a family of six related RASSF1-6 proteins (the classical RASSF proteins) and is expressed as three transcripts (A-C) via differential promoter usage and alternative splicing. All transcripts variants of RASSF5 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. RASSF5A is a pro-apoptotic Ras effector and functions as a Ras regulated tumor suppressor. RASSF5C is regulated by Ras related protein and modulates cellular adhesion.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 847141584 135 FVQMRTKLRSPGEVQK---LKSHRFSINGHFYNHKTSVFTPAyGSVTNVRVTSKMNTCQVLKLLLWKFRVENSPNEFAL- 210
Cdd:cd17220   33 FIKVHLKLRRPVTVPAgirPQSIYEVNPADTTDKRTSFYLPL-DAIKQLHISSTTTVSEVIQGLLKKFMVVDNPQKFALf 111

                         90       100
                 ....*....|....*....|....*....
gi 847141584 211 YLLHESGER--TKLGETEFPLICRILQGP 237
Cdd:cd17220  112 KRMRKDGQVlfQKLPLTEYPLYLRLLAGP 140

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 847141584 107 EELNNNANSRNTSEeeTPQLKRTRSDAS----FVQMRTKLRSPGEVQklkshrfSINGHFYNHKTSVFTPAyGSVTNVRV 182
Cdd:cd17219    2 EEIKQKIQLYNLAV--TDKLKMTLNSSGiytgFIKVQMDLRRPITVR-------GGAAGNNNNETAFYLPK-GSVNTLHI 71

                         90       100       110       120       130
                 ....*....|....*....|....*....|....*....|....*....|....*....
gi 847141584 183 TSKMNTCQVLKLLLWKFRVENSPNEFALYLLHESGERT---KLGETEFPLICRILQGPS 238
Cdd:cd17219   72 SSTNTVREVIEALLKKFLVADNPAKFALYKRCHKEDQVyacKLSDREHPLYLRLVAGPN 130

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 847141584 136 VQMRTKLRSPGEVQKLKSHRFSINGhfyNHKTSVFTPAyGSVTNVRVTSKMNTCQVLKLLLWKFRVENSPNEFALY--LL 213
Cdd:cd01778   17 ISVSAGTRPPSIYDVLKLEDSGDSR---KTRTSFYLPK-DTVKALHITSDTTAREVIEALLKKFKITDNPRKFALYerTH 92

                         90       100
                 ....*....|....*....|....*....
gi 847141584 214 HESGERT--KLGETEFPLICRILQGPSER 240
Cdd:cd01778   93 EEEGKVKlrKLSDDERPLYLCLLWGSQGD 121