Schultz et al. (1998) Proc. Natl. Acad. Sci. USA 95, 5857-5864
Letunic et al. (2012) Nucleic Acids Res , doi:10.1093/nar/gkr931

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RAS Ras subfamily of RAS small GTPases

SMART accession number:	SM00173
Description:	Similar in fold and function to the bacterial EF-Tu GTPase. p21Ras couples receptor Tyr kinases and G protein receptors to protein kinase cascades
Interpro abstract (IPR020849):	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. Ras proteins are small GTPases that regulate cell growth, proliferation and differentiation. The different Ras isoforms: H-ras, N-ras and K-ras, generate distinct signal outputs, despite interacting with a common set of activators and effectors. Ras is activated by guanine nucleotide exchange factors (GEFs) that release GDP and allow GTP binding. Many RasGEFs have been identified. These are sequestered in the cytosol until activation by growth factors triggers recruitment to the plasma membrane or Golgi, where the GEF colocalizes with Ras. Active GTP-bound Ras interacts with several effector proteins: among the best characterised are the Raf kinases, phosphatidylinositol 3-kinase (PI3K), RalGEFs and NORE/MST1. Ras proteins are synthesized as cytosolic precursors that undergo post-translational processing to be able to associate with cell membranes [(PUBMED:12728271)]. First, protein farnesyl transferase, a cytosolic enzyme, attaches a farnesyl group to the cysteine residue of the CAAX motif. Second, the farnesylated CAAX sequence targets Ras to the cytosolic surface of the ER where an endopeptidase removes the AAX tripeptide. Third, the alpha-carboxyl group on the now carboxy-terminal farnesylcysteine is methylated by isoprenylcysteine carboxyl methyltransferase. Finally, after methylation, Ras proteins take one of two routes to the cell surface, which is dictated by a second targeting signal that is located immediately amino-terminal to the farnesylated cysteine. N-ras and H-ras are expressed stably on the plasma membrane, on Golgi in transfected cells, and at least transiently on the ER. Ras has also been visualized on endosomes.
GO process:	signal transduction (GO:0007165), GTP catabolic process (GO:0006184)
GO component:	membrane (GO:0016020)
GO function:	GTP binding (GO:0005525), GTPase activity (GO:0003924)
Family alignment:	View or CHROMA formatCLUSTALW formatMSF formatFASTA formatPIR format

There are 1406 RAS domains in 1406 proteins in SMART's nrdb database.

Click on the following links for more information.

• Evolution (species in which this domain is found)

• Click on to expand nodes. To display all proteins with a RAS domain in a specific node, click on it.

  This tree shows only several representative species. The complete taxonomic breakdown of all proteins with RAS domain is also avaliable.

  Useful shortcuts: Expand all nodes or Collapse tree
  Go to specific node: Anopheles gambiae, Caenorhabditis elegans, Drosophila melanogaster, Homo sapiens, Mus musculus, Rattus norvegicus, Saccharomyces cerevisiae, Takifugu rubripes

• Cellular role (predicted cellular role)

• Binding / catalysis: GTP-hydrolysis

• Literature (relevant references for this domain)

• Primary literature is listed below; Automatically-derived, secondary literature is also avaliable.

  • Downward J
  • Ras signalling and apoptosis.
  • Curr Opin Genet Dev. 1998; 8: 49-54
  • Display abstract

  • Activated Ras proteins have either positive or negative effects on the regulation of apoptosis depending on cell type and other factors. In part, this is due to the ability of Ras to control directly multiple effector pathways, including PI3-kinase, which provides a universal survival signal, and Raf, which can inhibit survival. The mechanisms remain partly unclear, however, especially with regard to Raf effects on apoptosis regulation. Recently Ras has been shown to be able to protect cells from apoptosis either through activation of PKB/Akt via PI3-kinase, or through activation of NF-kappa B.

  • Lloyd AC
  • Ras versus cyclin-dependent kinase inhibitors.
  • Curr Opin Genet Dev. 1998; 8: 43-8
  • Display abstract

  • In the past year, complex interactions between Ras and the cell cycle have been identified. In primary cells, activated Ras induces a cell-cycle arrest via the induction of cyclin-dependent kinase inhibitors (CDKIs). Oncogenic changes that cooperate with Ras act by neutralising CDKIs by various mechanisms. In the absence of a negative growth signal from Ras, such as in most immortalised cell lines, Ras acts positively on the cell cycle. Insights have been made into the mechanisms by which Ras abrogates remaining cell-cycle controls.

  • Wittinghofer A, Pai EF
  • The structure of Ras protein: a model for a universal molecular switch.
  • Trends Biochem Sci. 1991; 16: 382-7
  • Display abstract

  • X-ray crystallography has revealed the molecular architecture of the cellular and oncogenic forms of p21Ha-ras, the protein encoded by the human Ha-ras gene, in both its active (GTP-bound) and in its inactive (GDP-bound) forms. From comparison of these two structures, a mechanism is suggested for the GTPase hydrolysis reaction that triggers the conformational change necessary for signal transduction. The structures have also allowed identification of the structural consequences of point mutations and the way in which they interfere with the intrinsic GTPase activity of p21ras. The p21ras structure is similar to that of the G-domain of elongation factor Tu (EF-Tu) from Escherichia coli, suggesting that p21ras can serve as a good model for other guanine nucleotide binding proteins.

  • Schlichting I et al.
  • Time-resolved X-ray crystallographic study of the conformational change in Ha-Ras p21 protein on GTP hydrolysis.
  • Nature. 1990; 345: 309-15
  • Display abstract

  • Crystals of Ha-Ras p21 with caged GTP at the active site have been used to investigate the conformational changes of p21 on GTP hydrolysis. The structure of the short-lived p21.GTP complex was determined by Laue diffraction methods. After GTP hydrolysis, substantial structural changes occur in the parts of the molecule implicated in the interaction with GTPase-activating protein. The trigger for this process seems to be a change in coordination of the active-site Mg2+ ion as a result of loss of the gamma-phosphate of GTP.

  • Pai EF, Kabsch W, Krengel U, Holmes KC, John J, Wittinghofer A
  • Structure of the guanine-nucleotide-binding domain of the Ha-ras oncogene product p21 in the triphosphate conformation.
  • Nature. 1989; 341: 209-14
  • Display abstract

  • The crystal structure of the guanine-nucleotide-binding domain of p21 (amino acids 1-166) complexed to the guanosine triphosphate analogue guanosine-5'-(beta, gamma-imido)triphosphate (GppNp) has been determined at a resolution of 2.6 A. The topological order of secondary structure elements is the same as that of the guanine-nucleotide-binding domain of bacterial elongation factor EF-Tu. Many interactions between nucleotide and protein have been identified. The effects of point mutations and the conservation of amino-acid sequence in the guanine-nucleotide-binding proteins are discussed.

  • Shih TY, Papageorge AG, Stokes PE, Weeks MO, Scolnick EM
  • Guanine nucleotide-binding and autophosphorylating activities associated with the p21src protein of Harvey murine sarcoma virus.
  • Nature. 1980; 287: 686-91
  • Display abstract

  • The purified p21src protein of Harvey sarcoma virus shows a guanine nucleotide-binding activity and, in addition, at elevated temperature an autophosphorylating activity at a threonine residue using as phosphoryl donor GTP or dGTP but not ATP or dATP. These biochemical activities are unique among those associated with transforming proteins of RNA-containing or DNA-containing tumour viruses.

• Disease (disease genes where sequence variants are found in this domain)

• SwissProt sequences and OMIM curated human diseases associated with missense mutations within the RAS domain.

  Protein	Disease
  Ras-related protein Rab-27A (P51159) (SMART)	OMIM:603868: Griscelli syndrome OMIM:214450:
  GTPase NRas (P01111) (SMART)	OMIM:164790: Colorectal cancer
  GTPase KRas, N-terminally processed (P01116) (SMART)	OMIM:190070: Colorectal adenoma ; Colorectal cancer
  Isoform 2B of GTPase KRas (P01116-2) (SMART)	OMIM:190070: Colorectal adenoma ; Colorectal cancer
  Ras-related protein R-Ras2 (P62070) (SMART)	OMIM:600098: ONCOGENE TC21
  GTPase HRas, N-terminally processed (P01112) (SMART)	OMIM:190020: Bladder cancer OMIM:109800:

• Metabolism (metabolic pathways involving proteins which contain this domain)

• % proteins involved KEGG pathway ID Description 6.97 map04010 MAPK signaling pathway 5.61 map04530 Tight junction 5.61 map04810 Regulation of actin cytoskeleton 4.55 map04910 Insulin signaling pathway 4.24 map05211 Renal cell carcinoma 4.24 map04720 Long-term potentiation 2.88 map05219 Bladder cancer 2.88 map05216 Thyroid cancer 2.88 map04664 Fc epsilon RI signaling pathway 2.88 map05213 Endometrial cancer 2.88 map04370 VEGF signaling pathway 2.88 map04912 GnRH signaling pathway 2.88 map04662 B cell receptor signaling pathway 2.88 map05212 Pancreatic cancer 2.88 map05220 Chronic myeloid leukemia 2.88 map05215 Prostate cancer 2.88 map05214 Glioma 2.88 map04012 ErbB signaling pathway 2.88 map04660 T cell receptor signaling pathway 2.88 map04540 Gap junction 2.88 map05221 Acute myeloid leukemia 2.88 map04916 Melanogenesis 2.88 map04730 Long-term depression 2.88 map04360 Axon guidance 2.88 map05223 Non-small cell lung cancer 2.88 map05218 Melanoma 2.88 map04650 Natural killer cell mediated cytotoxicity 2.12 map04510 Focal adhesion 1.67 map04150 mTOR signaling pathway 1.36 map04670 Leukocyte transendothelial migration 1.06 map05210 Colorectal cancer 1.06 map04320 Dorso-ventral axis formation 1.06 map04914 Progesterone-mediated oocyte maturation This information is based on mapping of SMART genomic protein database to KEGG orthologous groups. Percentage points are related to the number of proteins with RAS domain which could be assigned to a KEGG orthologous group, and not all proteins containing RAS domain. Please note that proteins can be included in multiple pathways, ie. the numbers above will not always add up to 100%.

• Structure (3D structures containing this domain)

• 3D Structures of RAS domains in PDB

  PDB code	Main view	Title
  121p		Struktur und guanosintriphosphat-hydrolysemechanismus des c- terminal verkuerzten menschlichen krebsproteins p21-h-ras
  1aa9		Human c-ha-ras(1-171)(dot)gdp, nmr, minimized average structure
  1agp		Three-dimensional structures and properties of a transforming and a nontransforming gly-12 mutant of p21-h- ras
  1bkd		Complex of human h-ras with human sos-1
  1c1y		Crystal structure of rap.gmppnp in complex with the ras- binding-domain of c-raf1 kinase (rafrbd).
  1clu		H-ras complexed with diaminobenzophenone-beta,gamma-imido- gtp
  1crp		The solution structure and dynamics of ras p21. gdp determined by heteronuclear three and four dimensional nmr spectroscopy
  1crq		The solution structure and dynamics of ras p21. gdp determined by heteronuclear three and four dimensional nmr spectroscopy
  1crr		The solution structure and dynamics of ras p21. gdp determined by heteronuclear three and four dimensional nmr spectroscopy
  1ctq		Structure of p21ras in complex with gppnhp at 100 k
  1gnp		X-ray crystal structure analysis of the catalytic domain of the oncogene product p21h-ras complexed with caged gtp and mant dgppnhp
  1gnq		X-ray crystal structure analysis of the catalytic domain of the oncogene product p21h-ras complexed with caged gtp and mant dgppnhp
  1gnr		X-ray crystal structure analysis of the catalytic domain of the oncogene product p21h-ras complexed with caged gtp and mant dgppnhp
  1gua		Human rap1a, residues 1-167, double mutant (e30d,k31e) complexed with gppnhp and the ras-binding-domain of human c-raf1, residues 51-131
  1he8		Ras g12v - pi 3-kinase gamma complex
  1iaq		C-h-ras p21 protein mutant with thr 35 replaced by ser (t35s) complexed with guanosine-5'-[b,g-imido] triphosphate
  1ioz		Crystal structure of the c-ha-ras protein prepared by the cell-free synthesis
  1jah		H-ras p21 protein mutant g12p, complexed with guanosine-5'- [beta,gamma-methylene] triphosphate and magnesium
  1jai		H-ras p21 protein mutant g12p, complexed with guanosine-5'- [beta,gamma-methylene] triphosphate and manganese
  1k8r		Crystal structure of ras-bry2rbd complex
  1kao		Crystal structure of the small g protein rap2a with gdp
  1lf0		Crystal structure of rasa59g in the gtp-bound form
  1lf5		Crystal structure of rasa59g in the gdp-bound form
  1lfd		Crystal structure of the active ras protein complexed with the ras-interacting domain of ralgds
  1nvu		Structural evidence for feedback activation by rasgtp of the ras-specific nucleotide exchange factor sos
  1nvv		Structural evidence for feedback activation by rasgtp of the ras-specific nucleotide exchange factor sos
  1nvw		Structural evidence for feedback activation by rasgtp of the ras-specific nucleotide exchange factor sos
  1nvx		Structural evidence for feedback activation by rasgtp of the ras-specific nucleotide exchange factor sos
  1p2s		H-ras 166 in 50% 2,2,2 triflouroethanol
  1p2t		H-ras 166 in aqueous mother liqour, rt
  1p2u		H-ras in 50% isopropanol
  1p2v		H-ras 166 in 60 % 1,6 hexanediol
  1plj		Crystallographic studies on p21h-ras using synchrotron laue method: improvement of crystal quality and monitoring of the gtpase reaction at different time points
  1plk		Crystallographic studies on p21h-ras using synchrotron laue method: improvement of crystal quality and monitoring of the gtpase reaction at different time points
  1pll		Crystallographic studies on p21h-ras using synchrotron laue method: improvement of crystal quality and monitoring of the gtpase reaction at different time points
  1q21		Crystal structures at 2.2 angstroms resolution of the catalytic domains of normal ras protein and an oncogenic mutant complexed with gsp
  1qra		Structure of p21ras in complex with gtp at 100 k
  1rvd		H-ras complexed with diaminobenzophenone-beta,gamma-imido- gtp
  1u8y		Crystal structures of ral-gppnhp and ral-gdp reveal two novel binding sites that are also present in ras and rap
  1u8z		Crystal structures of ral-gppnhp and ral-gdp reveal two novel binding sites that are also present in ras and rap
  1u90		Crystal structures of ral-gppnhp and ral-gdp reveal two novel binding sites that are also present in ras and rap
  1uad		Crystal structure of the rala-gppnhp-sec5 ral-binding domain complex
  1wq1		Ras-rasgap complex
  1x1r		Crystal structure of m-ras in complex with gdp
  1x1s		Crystal structure of m-ras in complex with gppnhp
  1xcm		Crystal structure of the gppnhp-bound h-ras g60a mutant
  1xd2		Crystal structure of a ternary ras:sos:ras*gdp complex
  1xj0		Crystal structure of the gdp-bound form of the rasg60a mutant
  1xtq		Structure of small gtpase human rheb in complex with gdp
  1xtr		Structure of small gtpase human rheb in complex with gppnhp
  1xts		Structure of small gtpase human rheb in complex with gtp
  1zc3		Crystal structure of the ral-binding domain of exo84 in complex with the active rala
  1zc4		Crystal structure of the ral-binding domain of exo84 in complex with the active rala
  1zvq		Structure of the q61g mutant of ras in the gdp-bound form
  1zw6		Crystal structure of the gtp-bound form of rasq61g
  221p		Three-dimensional structures of h-ras p21 mutants: molecular basis for their inability to function as signal switch molecules
  2a78		Crystal structure of the c3bot-rala complex reveals a novel type of action of a bacterial exoenzyme
  2a9k		Crystal structure of the c3bot-nad-rala complex reveals a novel type of action of a bacterial exoenzyme
  2atv		The crystal structure of human rerg in the gdp bound state
  2bov		Molecular recognition of an adp-ribosylating clostridium botulinum c3 exoenzyme by rala gtpase
  2c5l		Structure of plc epsilon ras association domain with hras
  2ce2		Crystal structure analysis of a fluorescent form of h-ras p21 in complex with gdp
  2cl0		Crystal structure analysis of a fluorescent form of h-ras p21 in complex with gppnhp
  2cl6		Crystal structure analysis of a fluorescent form of h-ras p21 in complex with s-caged gtp
  2cl7		Crystal structure analysis of a fluorescent form of h-ras p21 in complex with gtp
  2clc		Crystal structure analysis of a fluorescent form of h-ras p21 in complex with gtp (2)
  2cld		Crystal structure analysis of a fluorescent form of h-ras p21 in complex with gdp (2)
  2erx		Crystal structure of diras2 in complex with gdp and inorganic phosphate
  2ery		The crystal structure of the ras related protein rras2 (rras2) in the gdp bound state
  2evw		Crystal structure analysis of a fluorescent form of h-ras p21 in complex with r-caged gtp
  2fn4		The crystal structure of human ras-related protein, rras, in the gdp-bound state
  2gf0		The crystal structure of the human diras1 gtpase in the inactive gdp bound state
  2ke5		Solution structure and dynamics of the small gtpase ralb in its active conformation: significance for effector protein binding
  2q21		Crystal structures at 2.2 angstroms resolution of the catalytic domains of normal ras protein and an oncogenic mutant complexed with gsp
  2quz		Crystal structure of the activating h-rask117r mutant in costello syndrome, bound to mg-gdp
  2rap		The small g protein rap2a in complex with gtp
  2rga		Crystal structure of h-rasq61i-gppnhp
  2rgb		Crystal structure of h-rasq61k-gppnhp
  2rgc		Crystal structure of h-rasq61v-gppnhp
  2rgd		Crystal structure of h-rasq61l-gppnhp
  2rge		Crystal structure of h-ras-gppnhp
  2rgg		Crystal structure of h-rasq61i-gppnhp, trigonal crystal form
  2rhd		Crystal structure of cryptosporidium parvum small gtpase rab1a
  2uzi		Crystal structure of hras(g12v) - anti-ras fv complex
  2vh5		Crystal structure of hras(g12v) - anti-ras fv (disulfide free mutant) complex
  3brw		Structure of the rap-rapgap complex
  3cf6		Structure of epac2 in complex with cyclic-amp and rap
  3con		Crystal structure of the human nras gtpase bound with gdp
  3ddc		Crystal structure of nore1a in complex with ras
  3gft		Human k-ras in complex with a gtp analogue
  3rap		The small g protein rap2 in a non catalytic complex with gtp
  421p		Three-dimensional structures of h-ras p21 mutants: molecular basis for their inability to function as signal switch molecules
  4q21		Molecular switch for signal transduction: structural differences between active and inactive forms of protooncogenic ras proteins
  521p		Three-dimensional structures of h-ras p21 mutants: molecular basis for their inability to function as signal switch molecules
  5p21		Refined crystal structure of the triphosphate conformation of h-ras p21 at 1.35 angstroms resolution: implications for the mechanism of gtp hydrolysis
  621p		Three-dimensional structures of h-ras p21 mutants: molecular basis for their inability to function as signal switch molecules
  6q21		Molecular switch for signal transduction: structural differences between active and inactive forms of protooncogenic ras proteins
  721p		Three-dimensional structures of h-ras p21 mutants: molecular basis for their inability to function as signal switch molecules
  821p		Three-dimensional structures and properties of a transforming and a nontransforming glycine-12 mutant of p21h-ras

• Links (links to other resources describing this domain)

• PFAM	ras
  INTERPRO	IPR020849

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