|Complex of Rho GDP-dissociation inhibitor 2 (yellow) with G-protein RAC2 (red)|
|Available PDB structures:
2folA:13-174 1ukvY:10-171 1yznA:10-171 2bcgY:10-171 1g17B:22-182 1g16C:22-182 3rabA:24-185 1zbdA:24-185 2ew1A:11-172 1x3sA:10-171 1z0kA:10-171 2bmeA:10-171 2bmdA:10-171 1yu9A:10-171 2aedA:13-174 1z0fA:13-174 1z0aD:8-169 2a5jA:8-169 1oivB:13-172 1yzkA:13-174 1oixA:13-172 1oiwA:13-172 1z06A:35-201 1huqA:23-182 1z0dC:23-183 1z07A:23-182 1r2qA:22-183 1n6rA:22-183 1ek0A:9-173 1yvdA:7-168 1z0jA:7-168 2fg5A:7-168 1z08A:21-182 1yztB:21-182 1yzuB:21-182 1z0iA:21-182 1yzqA:15-176 1d5cA:13-172 1t91C:10-175 1vg8D:10-175 1vg9H:10-175 1vg1A:10-175 1vg0B:10-175 1ky3A:10-178 1ky2A:10-178 1yzlA:9-174 1wmsB:9-174 1s8fB:9-174 2f7sA:11-183 1z22A:11-171 1z2aA:11-171 1plj :5-165 1ctqA:5-165 1crp :5-165 821p :5-165 2eryB:16-177 2fn4A:31-192 1x1sA:15-177 1x1rA:15-177 1u90A:16-177 1u8zA:16-177 1u8yB:16-177 1uadB:16-177 2bovA:16-177 2a78A:16-177 3rapR:5-166 1kao :5-166 2rap :5-166 1c1yA:5-167 1guaA:5-167 1xtrA:8-169 1xtqA:8-169 1xtsA:8-169 2erxB:9-171 1a4rB:5-178 1kmqA:7-180 1tx4B:7-179 1cxzA:7-180 1m7bA:25-199 1gwnA:25-199 2bkuA:12-170 3ranA:12-170 1qg4B:12-170 1byuA:12-170 2atvA:8-169
In molecular biology, Ras is the name of a protein, the gene that encodes it, and the family and superfamily of proteins to which it belongs. The Ras superfamily of small GTPases includes the Ras, Rho, Arf, Rab, and Ran families.
Proteins in the Ras family are very important molecular switches for a wide variety of signal pathways that control such processes as cytoskeletal integrity, proliferation, cell adhesion, apoptosis, and cell migration.
Ras and ras-related proteins are often deregulated in cancers, leading to increased invasion and metastasis, and decreased apoptosis.
RAS activates a number of pathways but an especially important one seems to be the mitogen-activated protein (MAP) kinases, which themselves transmit signals downstream to other protein kinases and gene regulatory proteins.
Activated and inactivated forms
It is activated by guanine exchange factors (GEFs, eg. CDC25, SOS1 and SOS2, SDC25 in yeast), which are themselves activated by mitogenic signals and through feedback from Ras itself. A GEF usually heightens the dissociation rate of the nucleotide – while not changing the association rate (effectively lower the affinity of the nucleotide) – thereby promoting its exchange. The cellular concentration of GTP is much higher than that of GDP so the exchange is usually GDP vs. GTP.
It is inactivated by GTPase-activating proteins (GAPs, the most frequently cited one being RasGAP), which increase the rate of GTP hydrolysis, returning RAS to its GDP-bound form, simultaneously releasing an inorganic phosphate.
Ras is attached to the cell membrane by prenylation, and in health is a key component in many pathways which couple growth factor receptors to downstream mitogenic effectors involved in cell proliferation or differentiation. The C-terminal CaaX box of Ras first gets farnesylated at its Cys residue in the cytosol and then inserted into the membrane of the endoplasmatic reticulum. The Tripeptid (aaX) is then cleaved from the C-terminus by a specific prenyl-protein specific endoprotease, the new C-terminus is the methylated by a methyltransferase. The so processed Ras is now transported to the plasma membrane. Most Ras forms are now further palmityolated, while K-Ras with its long positively charged stretch interacts electrostaticly with the membrane.
Ras in cancer
Inappropriate activation of the gene
Inappropriate activation of the gene has been shown to play a key role in signal transduction, proliferation and malignant transformation.
Mutations in a number of different genes as well as RAS itself can have this effect. Oncogenes such as p210BCR-ABL or the growth receptor erbB are upstream of Ras, so if they are constitutively activated their signals will transduce through Ras.
The tumour suppressor gene NF1 encodes a Ras-GAP – its mutation in neurofibromatosis will mean that Ras is less likely to be inactivated. Ras can also be amplified, although this only occurs occasionally in tumours.
Finally, Ras oncogenes can be activated by point mutations so that its GTPase reaction can no longer be stimulated by GAP – this increases the half life of active Ras-GTP mutants.
Constitutively active Ras
Constitutively active Ras (RasD) is one which contains mutations that prevent GTP hydrolysis, thus locking Ras in a permanently 'On' state.
The most common mutations are found at residue G12 in the P-loop and the catalytic residue Q61.
- The glycine to valine mutation at residue 12 renders the GTPase domain of Ras insensitive to activation by GAP and thus stuck in the "on state". Ras requires a GAP for inactivation as it is a relatively poor catalyst on its own, as opposed to other G-domain-containing proteins such as the alpha subunit of heterotrimeric G proteins.
- Residue 61 is responsible for stabilizing the transition state for GTP hydrolysis. Because enzyme catalysis in general is achieved by lowering the energy barrier between substrate and product, mutation of Q61 necessarily reduces the rate of intrinsic Ras GTP hydrolysis to physiologically meaningless levels.
See also "dominant negative" mutants such as S17N and D119N.
Human proteins containing Ras domain
ARHE; ARHGAP5; CDC42; DIRAS1; DIRAS2; DIRAS3; ERAS; GEM; GRLF1; HRAS; KRAS; LOC393004; MRAS; NKIRAS1; NRAS; RAB10; RAB11A; RAB11B; RAB12; RAB13; RAB14; RAB15; RAB17; RAB18; RAB19; RAB1A; RAB1B; RAB2; RAB20; RAB21; RAB22A; RAB23; RAB24; RAB25; RAB26; RAB27A; RAB27B; RAB28; RAB2B; RAB30; RAB31; RAB32; RAB33A; RAB33B; RAB34; RAB35; RAB36; RAB37; RAB38; RAB39; RAB39B; RAB3A; RAB3B; RAB3C; RAB3D; RAB40A; RAB40AL; RAB40B; RAB40C; RAB41; RAB42; RAB43; RAB4A; RAB4B; RAB5A; RAB5B; RAB5C; RAB6A; RAB6B; RAB6C; RAB7A; RAB7B; RAB7L1; RAB8A; RAB8B; RAB9; RAB9B; RABL2A; RABL2B; RABL4; RAC1; RAC2; RAC3; RALA; RALB; RAN; RANP1; RAP1A; RAP1B; RAP2A; RAP2B; RAP2C; RASD1; RASD2; RASEF; RASL11A; RASL12; RBJ; REM1; REM2; RERG; RHEB; RHEBL1; RHOA; RHOB; RHOBTB1; RHOBTB2; RHOC; RHOD; RHOF; RHOG; RHOH; RHOJ; RHOQ; RHOU; RHOV; RIT1; RIT2; RND1; RND2; RND3; RRAD; RRAS; RRAS2; TC4;
- Shih, C. and Weinberg, R.A. (1982). "Isolation of a transforming sequence from a human bladder carcinoma cell line". Cell. 29: 161–169.
- Lodish H, Berk A, Zipursky SL, Matsudaira P, Baltimore D, Darnell J (2000). "Chapter 25, Cancer". Molecular cell biology (4th ed.). San Francisco: W.H. Freeman. ISBN 0-7167-3706-X.
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