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663  structures 1006  species 30  interactions 21243  sequences 332  architectures

Family: Ras (PF00071)

Summary: Ras family

Pfam includes annotations and additional family information from a range of different sources. These sources can be accessed via the tabs below.

This is the Wikipedia entry entitled "Ras subfamily". More...

Ras subfamily Edit Wikipedia article

This article is about p21/Ras protein. For the p21/waf1 protein, see p21.
Hras surface colored by conservation.png
H-Ras structure PDB 121p, surface colored by conservation in Pfam seed alignment: gold, most conserved; dark cyan, least conserved.
Identifiers
Symbol Ras
Pfam PF00071
InterPro IPR013753
PROSITE PDOC00017
SCOP 5p21
SUPERFAMILY 5p21
OPM protein 1uad
CDD cd04138

Ras is the name given to a family of related proteins which is ubiquitously expressed in all cell lineages and organs. All Ras protein family members belong to a class of protein called small GTPase, and are involved in transmitting signals within cells (cellular signal transduction). Ras is the prototypical member of the Ras superfamily of proteins, which are all related in 3D structure and regulate diverse cell behaviours.

The name 'Ras' is an abbreviation of 'Rat sarcoma', reflecting the way the first members of the protein family were discovered. The name ras is also used to refer to the family of genes encoding those proteins.

When Ras is 'switched on' by incoming signals, it subsequently switches on other proteins, which ultimately turn on genes involved in cell growth, differentiation and survival. As a result, mutations in ras genes can lead to the production of permanently activated Ras proteins. This can cause unintended and overactive signalling inside the cell, even in the absence of incoming signals.

Because these signals result in cell growth and division, overactive Ras signaling can ultimately lead to cancer.[1] The 3 Ras genes in humans (HRAS, KRAS, and NRAS) are the most common oncogenes in human cancer; mutations that permanently activate Ras are found in 20% to 25% of all human tumors and up to 90% in certain types of cancer (e.g., pancreatic cancer).[2] For this reason, Ras inhibitors are being studied as a treatment for cancer, and other diseases with Ras overexpression.

History

The first two ras genes, HRAS and KRAS, were first identified[3] from studies of two cancer-causing viruses, the Harvey sarcoma virus and Kirsten sarcoma virus, by Edward M. Scolnick and colleagues at the National Institutes of Health (NIH).[4] These viruses were discovered originally in rats during the 1960s by Jennifer Harvey[5] and Werner Kirsten,[6] respectively, hence the name Rat sarcoma. In 1982, activated and transforming human ras genes were discovered in human cancer cells by Geoffrey M. Cooper at Harvard,[7] Mariano Barbacid and Stuart A. Aaronson at the NIH,[8] Robert Weinberg at MIT,[9] and Michael Wigler at Cold Spring Harbor Laboratory.[10] A third ras gene was subsequently discovered by researchers in the group of Robin Weiss at the Institute of Cancer Research,[11][12] and Michael Wigler at Cold Spring Harbor Laboratory,[13] named NRAS, for its initial identification in human neuroblastoma cells.

The three human ras genes encode extremely similar proteins made up of chains of 188 to 189 amino acids, designated H-Ras, N-Ras and K-Ras4A and K-Ras4B (the two K-Ras proteins arise from alternative splicing).

Structure

H-Ras structure PDB 121p, ribbon showing strands in purple, helices in aqua, loops in gray. Also shown are the bound GTP analog and magnesium ion.

Ras contains a six-stranded beta sheet and 5 alpha helices:[14]

  • G domain (166 amino acids) which binds guanosine nucleotides, about 20kDa.
  • C terminal membrane targeting region (CAAX-COOH, also known as CAAX box) which is lipid-modified by farnesyl transferase, RCE1 and ICMT

The G domain contains five G motifs that bind GDP/GTP directly

  • G1 - P-loop binds the beta phosphate of GDP and GTP
  • G2 - Also called Switch I,consists of Threonine-35 that binds the terminal phosphate (γ-phosphate) of GTP and the divalent Magnesium ion present in the active site, but makes no contacts with GDP
  • G3 - Called the Switch II, has the DXXGQ motif, where the Aspartate-57 is specific for guanine binding rather than adenine and Glutamine-61 is the crucial residue that activates a catalytic water molecule for hydrolysis of GTP to GDP.
  • G4 - LVGNKxDL motif, provides specific interaction to guanine
  • G5 - SAK consensus sequence, the alanine-146 is specific for guanine rather than adenine

The two switch motifs, G2 and G3 are the main parts of the protein that move upon activation by GTP. This change in the conformation of the two switch motifs is what mediates the basic functionality as a molecular switch protein. This GTP bound state of Ras is On-state and GDP bound state is the Off-state.

Ras also binds a magnesium ion which helps to coordinate nucleotide binding.

Function

Overview of signal transduction pathways involved in apoptosis.

Ras proteins function as binary molecular switches that control intracellular signaling networks. Ras-regulated signal pathways control such processes as actin cytoskeletal integrity, proliferation, differentiation, 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 several pathways, of which the mitogen-activated protein (MAP) kinase cascade has been well-studied. This cascade transmits signals downstream and results in the transcription of genes involved in cell growth and division.[15] There is a separate AKT pathway that inhibits apoptosis.

Activation and deactivation

Ras is a G protein, or a guanosine-nucleotide-binding protein. Specifically, it is a single-subunit small GTPase, which is related in structure to the Gα subunit of heterotrimeric G proteins (large GTPases). G proteins function as binary signaling switches with "on" and "off" states. In the "off" state it is bound to the nucleotide guanosine diphosphate (GDP), while in the "on" state, Ras is bound to guanosine triphosphate (GTP), which has an extra phosphate group as compared to GDP. This extra phosphate holds the two switch regions in a "loaded-spring" configuration (specifically the Thr-35 and Gly-60). When released, the switch regions relax which causes a conformational change into the inactive state. Hence, activation and deactivation of Ras and other small G proteins are controlled by cycling between the active GTP-bound and inactive GDP-bound forms.

The process of exchanging the bound nucleotide is facilitated by guanine nucleotide exchange factors (GEFs) and GTPase activating proteins (GAPs). As per its classification, Ras has an intrinsic GTPase activity, which means that the protein on its own will hydrolyze a bound GTP molecule into GDP. However this process is too slow for efficient function, and hence the GAP for Ras, RasGAP, may bind to and stabilize the catalytic machinery of Ras, supplying additional catalytic residues ("arginine finger") such that a water molecule is optimally positioned for nucleophilic attack on the gamma-phosphate of GTP. An inorganic phosphate is released and the Ras molecule is now bound to a GDP. Since the GDP-bound form is "off" or "inactive" for signaling, GTPase Activating Protein inactivates Ras by activating its GTPase activity. Thus, GAPs accelerate Ras inactivation.

GEFs catalyze a "push and pull" reaction which releases GDP from Ras. They insert close to the P-loop and magnesium cation binding site and inhibit the interaction of these with the gamma phosphate anion. Acidic (negative) residues in switch II "pull" a lysine in the P-loop away from the GDP which "pushes" switch I away from the guanine. The contacts holding GDP in place are broken and it is released into the cytoplasm. Because intracellular GTP is abundant relative to GDP (approximately 10 fold more[15]) GTP predominantly re-enters the nucleotide binding pocket of Ras and reloads the spring. Thus GEFs facilitate Ras activation.[14] Well known GEFs include Son of Sevenless (Sos) and cdc25 which include the RasGEF domain.

The balance between GEF and GAP activity determines the guanine nucleotide status of Ras, thereby regulating Ras activity.

In the GTP-bound conformation, Ras has high affinity for numerous effectors which allow it to carry out its functions. These include PI3K. Other small GTPases may bind adaptors such as arfaptin or second messenger systems such as adenylyl cyclase. The Ras binding domain is found in many effectors and invariably binds to one of the switch regions, because these change conformation between the active and inactive forms. However, they may also bind to the rest of the protein surface.

Other proteins exist which may augment the activity of Ras family proteins. One example is GDI (GDP Disassociation Inhibitor); These function by slowing the exchange of GDP for GTP and thus, prolonging the inactive state of Ras family members. Other proteins that further augment this cycle may exist.

Membrane attachment

Ras is attached to the cell membrane owing to its prenylation and palmitoylation (HRAS and NRAS) or the combination of prenylation and a polybasic sequence adjacent to the prenylation site (KRAS). The C-terminal CaaX box of Ras first gets farnesylated at its Cys residue in the cytosol, allowing Ras to loosely insert into the membrane of the endoplasmatic reticulum and other cellular membranes. The Tripeptide (aaX) is then cleaved from the C-terminus by a specific prenyl-protein specific endoprotease and the new C-terminus is methylated by a methyltransferase. K-Ras procession is completed at this stage. Dynamic electrostatic interactions between its positively charged basic sequence with negative charges at the inner leaflet of the plasma membrane account for its predominant localization at the cell surface at steady-state. NRAS and HRAS are further processed on the surface of the Golgi apparatus by palmitoylation of one or two Cys residues, respectively, adjacent to the CaaX box. The proteins thereby become stably membrane anchored and are transported to the plasma membrane on vesicles of the secretory pathway. Depalmitoylation eventually releases the proteins from the membrane, allowing them to enter another cycle of palmitoylation and depalmitoylation.[16] This cycle is believed to prevent the leakage of NRAS and HRAS to other membranes over time and to maintain their steady-state localization along the Golgi apparatus, secretory pathway, plasma membrane and inter-linked endocytosis pathway.

Members

The clinically most notable members of the Ras subfamily are HRAS, KRAS and NRAS, mainly for being implicated in many types of cancer.[17]

However, there are many other members of this subfamily as well:[18] DIRAS1; DIRAS2; DIRAS3; ERAS; GEM; MRAS; NKIRAS1; NKIRAS2; NRAS; RALA; RALB; RAP1A; RAP1B; RAP2A; RAP2B; RAP2C; RASD1; RASD2; RASL10A; RASL10B; RASL11A; RASL11B; RASL12; REM1; REM2; RERG; RERGL; RRAD; RRAS; RRAS2

Ras in cancer

Mutations in the Ras family of proto-oncogenes (comprising H-Ras, N-Ras and K-Ras) are very common, being found in 20% to 30% of all human tumours.[17] it is reasonable to speculate that a pharmacological approach that curtails Ras activity may represent a possible method to inhibit certain cancer types. Ras point mutations are the single most common abnormality of human proto-oncogenes.[19] Ras inhibitor trans-farnesylthiosalicylic acid (FTS, Salirasib) exhibits profound anti-oncogenic effects in many cancer cell lines.[20][21]

Inappropriate activation

Inappropriate activation of the gene has been shown to play a key role in signal transduction, proliferation and malignant transformation.[15]

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 the GTPase reaction can no longer be stimulated by GAP – this increases the half life of active Ras-GTP mutants.[22]

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 inactivation 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[23] 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 to K necessarily reduces the rate of intrinsic Ras GTP hydrolysis to physiologically meaningless levels.

See also "dominant negative" mutants such as S17N and D119N.

Ras-targeted cancer treatments

Reovirus was noted to be a potential cancer therapeutic when early studies on reovirus suggested it reproduces well in certain cancer cell lines. It has since been shown to replicate specifically in cells that have an activated Ras pathway (a cellular signaling pathway that is involved in cell growth and differentiation).[24] Reovirus replicates in and eventually kills Ras-activated tumour cells and as cell death occurs, progeny virus particles are free to infect surrounding cancer cells. This cycle of infection, replication and cell death is believed to be repeated until all tumour cells carrying an activated Ras pathway are destroyed. Another tumor lysing virus that specifically targets tumor cells with an activated Ras pathway is a type II herpes simplex virus (HSV-2) based agent, designated FusOn-H2.[25] Activating mutations of the Ras protein and upstream elements of the Ras protein may play a role in more than two thirds of all human cancers, including most metastatic disease. Reolysin, a formulation of reovirus, and FusOn-H2 are currently in clinical trials or under development for the treatment of various cancers.[26] In addition, a treatment based on siRNA anti mutated K-RAS (G12D) called siG12D LODER is currently in clinical trials for the treatment of locally advanced pancreatic cancer (NCT01188785, NCT01676259).[27]

References

  1. ^ Goodsell DS (1999). "The molecular perspective: the ras oncogene". Oncologist 4 (3): 263–4. PMID 10394594. 
  2. ^ Downward J (January 2003). "Targeting RAS signalling pathways in cancer therapy". Nat. Rev. Cancer 3 (1): 11–22. doi:10.1038/nrc969. PMID 12509763. 
  3. ^ Malumbres M, Barbacid M (June 2003). "RAS oncogenes: the first 30 years". Nat. Rev. Cancer 3 (6): 459–65. doi:10.1038/nrc1097. PMID 12778136. 
  4. ^ Chang EH, Gonda MA, Ellis RW, Scolnick EM, Lowy DR (August 1982). "Human genome contains four genes homologous to transforming genes of Harvey and Kirsten murine sarcoma viruses". Proc. Natl. Acad. Sci. U.S.A. 79 (16): 4848–52. doi:10.1073/pnas.79.16.4848. PMC 346782. PMID 6289320. 
  5. ^ Harvey JJ (December 1964). "An unidentified virus which causes the rapid production of tumours in mice". Nature 204 (4963): 1104–5. doi:10.1038/2041104b0. PMID 14243400. 
  6. ^ Kirsten WH, Schauf V, McCoy J (1970). "Properties of a murine sarcoma virus". Bibl Haematol (36): 246–9. PMID 5538357. 
  7. ^ Cooper GM (August 1982). "Cellular transforming genes". Science 217 (4562): 801–6. doi:10.1126/science.6285471. PMID 6285471. 
  8. ^ Santos E, Tronick SR, Aaronson SA, Pulciani S, Barbacid M (July 1982). "T24 human bladder carcinoma oncogene is an activated form of the normal human homologue of BALB- and Harvey-MSV transforming genes". Nature 298 (5872): 343–7. doi:10.1038/298343a0. PMID 6283384. 
  9. ^ Parada LF, Tabin CJ, Shih C, Weinberg RA (June 1982). "Human EJ bladder carcinoma oncogene is homologue of Harvey sarcoma virus ras gene". Nature 297 (5866): 474–8. doi:10.1038/297474a0. PMID 6283357. 
  10. ^ Taparowsky E, Suard Y, Fasano O, Shimizu K, Goldfarb M, Wigler M (December 1982). "Activation of the T24 bladder carcinoma transforming gene is linked to a single amino acid change". Nature 300 (5894): 762–5. doi:10.1038/300762a0. PMID 7177195. 
  11. ^ Marshall CJ, Hall A, Weiss RA (September 1982). "A transforming gene present in human sarcoma cell lines". Nature 299 (5879): 171–3. doi:10.1038/299171a0. PMID 6287287. 
  12. ^ Hall A, Marshall CJ, Spurr NK, Weiss RA (1983). "Identification of transforming gene in two human sarcoma cell lines as a new member of the ras gene family located on chromosome 1". Nature 303 (5916): 396–400. doi:10.1038/303396a0. PMID 6304521. 
  13. ^ Shimizu K, Goldfarb M, Perucho M, Wigler M (January 1983). "Isolation and preliminary characterization of the transforming gene of a human neuroblastoma cell line". PNAS 80 (2): 383–7. doi:10.1073/pnas.80.2.383. PMID 6300838. 
  14. ^ a b Vetter IR, Wittinghofer A (November 2001). "The guanine nucleotide-binding switch in three dimensions". Science 294 (5545): 1299–304. doi:10.1126/science.1062023. PMID 11701921. 
  15. ^ a b c 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. 
  16. ^ Rocks O, Peyker A, Bastiaens PI (2006). "Spatio-temporal segregation of Ras signals: one ship, three anchors, many harbors". Current Opinion in Cell Biology 18 (4): 351–7. doi:10.1016/j.ceb.2006.06.007. PMID 16781855. 
  17. ^ a b Bos J (1989). "ras oncogenes in human cancer: a review". Cancer Res 49 (17): 4682–9. PMID 2547513. 
  18. ^ Wennerberg K, Rossman KL, Der CJ (March 2005). "The Ras superfamily at a glance". J. Cell. Sci. 118 (Pt 5): 843–6. doi:10.1242/jcs.01660. PMID 15731001. 
  19. ^ Robbins and Cotran (2010). Pathologic Basis of Disease 8th ed. p. 282. 
  20. ^ Rotblat B, Ehrlich M, Haklai R, Kloog Y (2008). "The Ras inhibitor farnesylthiosalicylic acid (Salirasib) disrupts the spatiotemporal localization of active Ras: a potential treatment for cancer.". Methods Enzymol 439: 467–89. doi:10.1016/S0076-6879(07)00432-6. PMID 18374183. 
  21. ^ Roy Blum, yoel kloog (2005). "Ras Inhibition in Glioblastoma Down-regulates Hypoxia-Inducible Factor-1, Causing Glycolysis Shutdown and Cell Death". Cancer Research 65 (3): 999–1006. PMID 15705901. 
  22. ^ Reuter C, Morgan M, Bergmann L (2000). "Targeting the Ras signaling pathway: a rational, mechanism-based treatment for hematologic malignancies?". Blood 96 (5): 1655–69. PMID 10961860. 
  23. ^ Omim - Neuroblastoma Ras Viral Oncogene Homolog; Nras
  24. ^ Lal R, Harris D, Postel-Vinay S, de Bono J (October 2009). "Reovirus: Rationale and clinical trial update". Curr. Opin. Mol. Ther. 11 (5): 532–9. PMID 19806501. 
  25. ^ Fu, Xinping; Prigge-J, Cai-R and Xiaoliu Zhang. "A mutant type 2 herpes simplex virus deleted for the protein kinase domain of the ICP10 gene is a potent oncolytic virus". Molecular Therapy 13 (5): 882–890. 
  26. ^ Thirukkumaran C, Morris DG (2009). "Oncolytic viral therapy using reovirus". Methods Mol. Biol. 542: 607–34. doi:10.1007/978-1-59745-561-9_31. PMID 19565924. 
  27. ^ "ClinicalTrials.gov". 

Further reading

External links

This page is based on a Wikipedia article. The text is available under the Creative Commons Attribution/Share-Alike License.

This is the Wikipedia entry entitled "Ras superfamily". More...

Ras superfamily Edit Wikipedia article

Hras surface colored by conservation.png
H-Ras structure PDB 121p, surface colored by conservation in Pfam seed alignment: gold, most conserved; dark cyan, least conserved.
Identifiers
Symbol Ras
Pfam PF00071
InterPro IPR013753
PROSITE PDOC00017
SCOP 5p21
SUPERFAMILY 5p21
OPM protein 1uad
CDD cd00882

The Ras superfamily is a protein superfamily of small GTPases, which are all related, to a degree, to the Ras protein subfamily (the key human members of which are KRAS, NRAS, and HRAS).

There are more than a hundred proteins in the Ras superfamily.[1] Based on structure, sequence and function, the Ras superfamily is divided into nine main families, each of which further divided into subfamilies: Ras, Rad, Rab, Rap, Ran, Rho, Rheb, Rit, and Arf. Miro is a recent contributor to the superfamily.

Each subfamily shares the common core G domain, which provides essential GTPase and nucleotide exchange activity.

The surrounding sequence helps determine the functional specificity of the small GTPase, for example the 'Insert Loop', common to the Rho subfamily, specifically contributes to binding to effector proteins such as IQGAP and WASP.

In general, the Ras family is responsible for cell proliferation: Rho for cell morphology, Ran for nuclear transport, and Rab and Arf for vesicle transport.[2]

Subfamilies and members

The following is a list of human proteins belonging to the Ras superfamily:[1]

Overview
Subfamily Function Members
Ras cell proliferation [2] DIRAS1; DIRAS2; DIRAS3; ERAS; GEM; HRAS; KRAS; MRAS; NKIRAS1; NKIRAS2; NRAS; RALA; RALB; RAP1A; RAP1B; RAP2A; RAP2B; RAP2C; RASD1; RASD2; RASL10A; RASL10B; RASL11A; RASL11B; RASL12; REM1; REM2; RERG; RERGL; RRAD; RRAS; RRAS2
Rho cytoskeletal dynamics/morphology[2] RHOA; RHOB; RHOBTB1; RHOBTB2; RHOBTB3; RHOC; RHOD; RHOF; RHOG; RHOH; RHOJ; RHOQ; RHOU; RHOV; RND1; RND2; RND3; RAC1; RAC2; RAC3; CDC42
Rab membrane trafficking RAB1A; RAB1B; RAB2; RAB3A; RAB3B; RAB3C; RAB3D; RAB4A; RAB4B; RAB5A; RAB5B; RAB5C; RAB6A; RAB6B; RAB6C; RAB7A; RAB7B; RAB7L1; RAB8A; RAB8B; RAB9; RAB9B; RABL2A; RABL2B; RABL4; RAB10; RAB11A; RAB11B; RAB12; RAB13; RAB14; RAB15; RAB17; RAB18; RAB19; RAB20; RAB21; RAB22A; RAB23; RAB24; RAB25; RAB26; RAB27A; RAB27B; RAB28; RAB2B; RAB30; RAB31; RAB32; RAB33A; RAB33B; RAB34; RAB35; RAB36; RAB37; RAB38; RAB39; RAB39B; RAB40A; RAB40AL; RAB40B; RAB40C; RAB41; RAB42; RAB43
Rap cellular adhesion RAP1A; RAP1B; RAP2A; RAP2B; RAP2C
Arf vesicular transport[2] ARF1; ARF3; ARF4; ARF5; ARF6; ARL1; ARL2; ARL3; ARL4; ARL5; ARL5C; ARL6; ARL7; ARL8; ARL9; ARL10A; ARL10B; ARL10C; ARL11; ARL13A; ARL13B; ARL14; ARL15; ARL16; ARL17; TRIM23, ARL4D; ARFRP1; ARL13B
Ran nuclear transport RAN
Rheb mTOR pathway RHEB; RHEBL1
RGK RRAD; GEM; REM; REM2
Rit RIT1; RIT2
Miro mitochondrial transport RHOT1; RHOT2

Unclassified:

See also

References

  1. ^ a b Wennerberg K, Rossman KL, Der CJ (March 2005). "The Ras superfamily at a glance". J. Cell. Sci. 118 (Pt 5): 843–6. doi:10.1242/jcs.01660. PMID 15731001. 
  2. ^ a b c d Munemitsu S, Innis M, Clark R, McCormick F, Ullrich A, Polakis P. (1990). "Molecular cloning and experssion of a G25K cDNA, the human homolog of the yeast cell cycle gene CDC42". Mol Cell Biol 10 (11): 5977–82. ISSN 0270-7306. PMC 361395. PMID 2122236. 

This page is based on a Wikipedia article. The text is available under the Creative Commons Attribution/Share-Alike License.

This tab holds the annotation information that is stored in the Pfam database. As we move to using Wikipedia as our main source of annotation, the contents of this tab will be gradually replaced by the Wikipedia tab.

Ras family Provide feedback

Includes sub-families Ras, Rab, Rac, Ral, Ran, Rap Ypt1 and more. Shares P-loop motif with GTP_EFTU, arf and myosin_head. See PF00009 PF00025 PF00063. As regards Rab GTPases, these are important regulators of vesicle formation, motility and fusion. They share a fold in common with all Ras GTPases: this is a six-stranded beta-sheet surrounded by five alpha-helices [1].

Literature references

  1. Stenmark H, Olkkonen VM; , Genome Biol 2001;2:REVIEWS3007.: The Rab GTPase family. PUBMED:11387043 EPMC:11387043


External database links

This tab holds annotation information from the InterPro database.

InterPro entry IPR001806

Small GTPases form an independent superfamily within the larger class of regulatory GTP hydrolases. This superfamily contains proteins that control a vast number of important processes and possess a common, structurally preserved GTP-binding domain [PUBMED:2122258, PUBMED:1898771]. Sequence comparisons of small G proteins from various species have revealed that they are conserved in primary structures at the level of 30-55% similarity [PUBMED:2029511].

Crystallographic analysis of various small G proteins revealed the presence of a 20 kDa catalytic domain that is unique for the whole superfamily [PUBMED:1898771, PUBMED:2196171]. The domain is built of five alpha helices (A1-A5), six beta-strands (B1-B6) and five polypeptide loops (G1-G5). A structural comparison of the GTP- and GDP-bound form, allows one to distinguish two functional loop regions: switch I and switch II that surround the gamma-phosphate group of the nucleotide. The G1 loop (also called the P-loop) that connects the B1 strand and the A1 helix is responsible for the binding of the phosphate groups. The G3 loop provides residues for Mg(2+) and phosphate binding and is located at the N terminus of the A2 helix. The G1 and G3 loops are sequentially similar to Walker A and Walker B boxes that are found in other nucleotide binding motifs. The G2 loop connects the A1 helix and the B2 strand and contains a conserved Thr residue responsible for Mg(2+) binding. The guanine base is recognised by the G4 and G5 loops. The consensus sequence NKXD of the G4 loop contains Lys and Asp residues directly interacting with the nucleotide. Part of the G5 loop located between B6 and A5 acts as a recognition site for the guanine base [PUBMED:11995995].

The small GTPase superfamily can be divided into at least 8 different families, including:

  • Arf small GTPases. GTP-binding proteins involved in protein trafficking by modulating vesicle budding and uncoating within the Golgi apparatus.
  • Ran small GTPases. GTP-binding proteins involved in nucleocytoplasmic transport. Required for the import of proteins into the nucleus and also for RNA export.
  • Rab small GTPases. GTP-binding proteins involved in vesicular traffic.
  • Rho small GTPases. GTP-binding proteins that control cytoskeleton reorganisation.
  • Ras small GTPases. GTP-binding proteins involved in signalling pathways.
  • Sar1 small GTPases. Small GTPase component of the coat protein complex II (COPII) which promotes the formation of transport vesicles from the endoplasmic reticulum (ER).
  • Mitochondrial Rho (Miro). Small GTPase domain found in mitochondrial proteins involved in mitochondrial trafficking.
  • Roc small GTPases domain. Small GTPase domain always found associated with the COR domain.

Gene Ontology

The mapping between Pfam and Gene Ontology is provided by InterPro. If you use this data please cite InterPro.

Domain organisation

Below is a listing of the unique domain organisations or architectures in which this domain is found. More...

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Pfam Clan

This family is a member of clan P-loop_NTPase (CL0023), which has the following description:

AAA family proteins often perform chaperone-like functions that assist in the assembly, operation, or disassembly of protein complexes [2].

The clan contains the following 198 members:

6PF2K AAA AAA-ATPase_like AAA_10 AAA_11 AAA_12 AAA_13 AAA_14 AAA_15 AAA_16 AAA_17 AAA_18 AAA_19 AAA_2 AAA_21 AAA_22 AAA_23 AAA_24 AAA_25 AAA_26 AAA_27 AAA_28 AAA_29 AAA_3 AAA_30 AAA_31 AAA_32 AAA_33 AAA_34 AAA_35 AAA_4 AAA_5 AAA_6 AAA_7 AAA_8 AAA_9 AAA_PrkA ABC_ATPase ABC_tran ABC_tran_2 Adeno_IVa2 Adenylsucc_synt ADK AFG1_ATPase AIG1 APS_kinase Arch_ATPase Arf ArgK ArsA_ATPase ATP-synt_ab ATP_bind_1 ATP_bind_2 Bac_DnaA CbiA CMS1 CoaE CobA_CobO_BtuR CobU cobW CPT CTP_synth_N Cytidylate_kin Cytidylate_kin2 DAP3 DEAD DEAD_2 DLIC DNA_pack_C DNA_pack_N DNA_pol3_delta DNA_pol3_delta2 DnaB_C dNK DUF1253 DUF1611 DUF2075 DUF2478 DUF258 DUF2791 DUF2813 DUF3584 DUF463 DUF815 DUF853 DUF87 DUF927 Dynamin_N Exonuc_V_gamma FeoB_N Fer4_NifH Flavi_DEAD FTHFS FtsK_SpoIIIE G-alpha Gal-3-0_sulfotr GBP GTP_EFTU GTP_EFTU_D2 GTP_EFTU_D4 Gtr1_RagA Guanylate_kin GvpD HDA2-3 Helicase_C Helicase_C_2 Helicase_C_4 Helicase_RecD Herpes_Helicase Herpes_ori_bp Herpes_TK IIGP IPPT IPT IstB_IS21 KaiC KAP_NTPase Kinesin Kinesin-relat_1 Kinesin-related KTI12 LpxK MCM MEDS Mg_chelatase Mg_chelatase_2 MipZ Miro MMR_HSR1 MobB MukB MutS_V Myosin_head NACHT NB-ARC NOG1 NTPase_1 ParA Parvo_NS1 PAXNEB PduV-EutP PhoH PIF1 Podovirus_Gp16 Polyoma_lg_T_C Pox_A32 PPK2 PPV_E1_C PRK Rad17 Rad51 Ras RecA ResIII RHD3 RHSP RNA12 RNA_helicase RuvB_N SbcCD_C SecA_DEAD Septin Sigma54_activ_2 Sigma54_activat SKI SMC_N SNF2_N Spore_IV_A SRP54 SRPRB Sulfotransfer_1 Sulfotransfer_2 Sulfotransfer_3 Sulphotransf T2SE T4SS-DNA_transf Terminase_1 Terminase_3 Terminase_6 Terminase_GpA Thymidylate_kin TIP49 TK TniB Torsin TraG-D_C tRNA_lig_kinase TrwB_AAD_bind UPF0079 UvrD-helicase UvrD_C UvrD_C_2 Viral_helicase1 VirC1 VirE YhjQ Zeta_toxin Zot

Alignments

We store a range of different sequence alignments for families. As well as the seed alignment from which the family is built, we provide the full alignment, generated by searching the sequence database using the family HMM. We also generate alignments using four representative proteomes (RP) sets, the NCBI sequence database, and our metagenomics sequence database. More...

View options

We make a range of alignments for each Pfam-A family. You can see a description of each above. You can view these alignments in various ways but please note that some types of alignment are never generated while others may not be available for all families, most commonly because the alignments are too large to handle.

  Seed
(61)
Full
(21243)
Representative proteomes NCBI
(30754)
Meta
(3385)
RP15
(4857)
RP35
(6747)
RP55
(9773)
RP75
(12839)
Jalview View  View  View  View  View  View  View  View 
HTML View    View           
PP/heatmap 1   View           
Pfam viewer View  View             

1Cannot generate PP/Heatmap alignments for seeds; no PP data available

Key: ✓ available, x not generated, not available.

Format an alignment

  Seed
(61)
Full
(21243)
Representative proteomes NCBI
(30754)
Meta
(3385)
RP15
(4857)
RP35
(6747)
RP55
(9773)
RP75
(12839)
Alignment:
Format:
Order:
Sequence:
Gaps:
Download/view:

Download options

We make all of our alignments available in Stockholm format. You can download them here as raw, plain text files or as gzip-compressed files.

  Seed
(61)
Full
(21243)
Representative proteomes NCBI
(30754)
Meta
(3385)
RP15
(4857)
RP35
(6747)
RP55
(9773)
RP75
(12839)
Raw Stockholm Download   Download   Download   Download   Download   Download   Download   Download  
Gzipped Download   Download   Download   Download   Download   Download   Download   Download  

You can also download a FASTA format file containing the full-length sequences for all sequences in the full alignment.

External links

MyHits provides a collection of tools to handle multiple sequence alignments. For example, one can refine a seed alignment (sequence addition or removal, re-alignment or manual edition) and then search databases for remote homologs using HMMER3.

HMM logo

HMM logos is one way of visualising profile HMMs. Logos provide a quick overview of the properties of an HMM in a graphical form. You can see a more detailed description of HMM logos and find out how you can interpret them here. More...

Trees

This page displays the phylogenetic tree for this family's seed alignment. We use FastTree to calculate neighbour join trees with a local bootstrap based on 100 resamples (shown next to the tree nodes). FastTree calculates approximately-maximum-likelihood phylogenetic trees from our seed alignment.

Note: You can also download the data file for the tree.

Curation and family details

This section shows the detailed information about the Pfam family. You can see the definitions of many of the terms in this section in the glossary and a fuller explanation of the scoring system that we use in the scores section of the help pages.

Curation View help on the curation process

Seed source: Swissprot
Previous IDs: ras;
Type: Domain
Author: Sonnhammer ELL, Fenech M
Number in seed: 61
Number in full: 21243
Average length of the domain: 151.90 aa
Average identity of full alignment: 29 %
Average coverage of the sequence by the domain: 62.64 %

HMM information View help on HMM parameters

HMM build commands:
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 23193494 -E 1000 --cpu 4 HMM pfamseq
Model details:
Parameter Sequence Domain
Gathering cut-off 20.8 20.8
Trusted cut-off 20.8 20.8
Noise cut-off 20.7 20.7
Model length: 162
Family (HMM) version: 17
Download: download the raw HMM for this family

Species distribution

Sunburst controls

Show

This visualisation provides a simple graphical representation of the distribution of this family across species. You can find the original interactive tree in the adjacent tab. More...

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Tree controls

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The tree shows the occurrence of this domain across different species. More...

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Please note: for large trees this can take some time. While the tree is loading, you can safely switch away from this tab but if you browse away from the family page entirely, the tree will not be loaded.

Interactions

There are 30 interactions for this family. More...

RhoGAP VPS9 PI3K_rbd TPR_1 RCC1 RBD Ras GDI Rho_Binding HEAT PH YopE PDZ HR1 NTF2 TIG RabGAP-TBC Rho_GDI IBN_N RasGEF PI3_PI4_kinase Ran_BP1 ADPrib_exo_Tox Mss4 Drf_GBD RBD-FIP Rbsn RasGEF_N RhoGEF RasGAP

Structures

For those sequences which have a structure in the Protein DataBank, we use the mapping between UniProt, PDB and Pfam coordinate systems from the PDBe group, to allow us to map Pfam domains onto UniProt sequences and three-dimensional protein structures. The table below shows the structures on which the Ras domain has been found. There are 663 instances of this domain found in the PDB. Note that there may be multiple copies of the domain in a single PDB structure, since many structures contain multiple copies of the same protein seqence.

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