| Structural highlights
Disease
[RASH_HUMAN] Defects in HRAS are the cause of faciocutaneoskeletal syndrome (FCSS) [MIM:218040]. A rare condition characterized by prenatally increased growth, postnatal growth deficiency, mental retardation, distinctive facial appearance, cardiovascular abnormalities (typically pulmonic stenosis, hypertrophic cardiomyopathy and/or atrial tachycardia), tumor predisposition, skin and musculoskeletal abnormalities.[1] [2] [3] [4] [5] [6] [7] Defects in HRAS are the cause of congenital myopathy with excess of muscle spindles (CMEMS) [MIM:218040]. CMEMS is a variant of Costello syndrome.[8] Defects in HRAS may be a cause of susceptibility to Hurthle cell thyroid carcinoma (HCTC) [MIM:607464]. Hurthle cell thyroid carcinoma accounts for approximately 3% of all thyroid cancers. Although they are classified as variants of follicular neoplasms, they are more often multifocal and somewhat more aggressive and are less likely to take up iodine than are other follicular neoplasms. Note=Mutations which change positions 12, 13 or 61 activate the potential of HRAS to transform cultured cells and are implicated in a variety of human tumors. Defects in HRAS are a cause of susceptibility to bladder cancer (BLC) [MIM:109800]. A malignancy originating in tissues of the urinary bladder. It often presents with multiple tumors appearing at different times and at different sites in the bladder. Most bladder cancers are transitional cell carcinomas. They begin in cells that normally make up the inner lining of the bladder. Other types of bladder cancer include squamous cell carcinoma (cancer that begins in thin, flat cells) and adenocarcinoma (cancer that begins in cells that make and release mucus and other fluids). Bladder cancer is a complex disorder with both genetic and environmental influences. Note=Defects in HRAS are the cause of oral squamous cell carcinoma (OSCC).[9] Defects in HRAS are the cause of Schimmelpenning-Feuerstein-Mims syndrome (SFM) [MIM:163200]. A disease characterized by sebaceous nevi, often on the face, associated with variable ipsilateral abnormalities of the central nervous system, ocular anomalies, and skeletal defects. Many oral manifestations have been reported, not only including hypoplastic and malformed teeth, and mucosal papillomatosis, but also ankyloglossia, hemihyperplastic tongue, intraoral nevus, giant cell granuloma, ameloblastoma, bone cysts, follicular cysts, oligodontia, and odontodysplasia. Sebaceous nevi follow the lines of Blaschko and these can continue as linear intraoral lesions, as in mucosal papillomatosis.[10]
Function
[RASH_HUMAN] Ras proteins bind GDP/GTP and possess intrinsic GTPase activity.[11] [12] [13]
Evolutionary Conservation
Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.
Publication Abstract from PubMed
The backbone 1H, 13C, and 15N resonances of the c-Ha-Ras protein [a truncated version consisting of residues 1-171, Ras(1-171)] bound with GMPPNP (a slowly hydrolyzable analogue of GTP) were assigned and compared with those of the GDP-bound Ras(1-171). The backbone amide resonances of amino acid residues 10-13, 21, 31-39, 57-64, and 71 of Ras(1-171).GMPPNP, but not those of Ras(1-171).GDP, were extremely broadened, whereas other residues of Ras(1-171).GMPPNP exhibited amide resonances nearly as sharp as those of Ras(1-171). GDP. The residues exhibiting the extreme broadening, except for residues 21 and 71, are localized in three functional loop regions [loops L1, L2 (switch I), and L4 (switch II)], which are involved in hydrolysis of GTP and interactions with other proteins. From the temperature and magnetic field strength dependencies of the backbone amide resonance intensities, the extreme broadening was ascribed to the exchange at an intermediate rate on the NMR time scale. It was shown that the Ras(1-171) protein bound with GTP or GTPgammaS (another slowly hydrolyzable analogue of GTP) exhibits the same type of broadening. Therefore, it is a characteristic feature of the GTP-bound form of Ras that the L1, L2, and L4 loop regions, but not other regions, are in a rather slow interconversion between two or more stable conformers. This phenomenon, termed a "regional polysterism", of these loop regions may be related with their multifunctionality: the GTP-dependent interactions with several downstream target groups such as the Raf and RalGDS families and also with the GTPase activating protein (GAP) family. In fact, the binding of Ras(1-171).GMPPNP with the Ras-binding domain (residues 51-131) of c-Raf-1 was shown to eliminate the regional polysterism nearly completely. It was indicated, therefore, that each target/regulator selects its appropriate conformer among those presented by the "polysteric" binding interface of Ras. As the downstream target groups exhibit no apparent sequence homology to each other, it is possible that one target group prefers a conformer different from that preferred by another group. The involvement of loop L1 in the regional polysterism might suggest that the negative regulators, GAPs, bind to the polysteric binding interface (loops L2 and L4) of Ras and cooperatively select a conformer suitable for transition of the GTPase catalytic center, involving loops L1 and L4, into the highly active state.
Regional polysterism in the GTP-bound form of the human c-Ha-Ras protein.,Ito Y, Yamasaki K, Iwahara J, Terada T, Kamiya A, Shirouzu M, Muto Y, Kawai G, Yokoyama S, Laue ED, Walchli M, Shibata T, Nishimura S, Miyazawa T Biochemistry. 1997 Jul 29;36(30):9109-19. PMID:9230043[14]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Aoki Y, Niihori T, Kawame H, Kurosawa K, Ohashi H, Tanaka Y, Filocamo M, Kato K, Suzuki Y, Kure S, Matsubara Y. Germline mutations in HRAS proto-oncogene cause Costello syndrome. Nat Genet. 2005 Oct;37(10):1038-40. Epub 2005 Sep 18. PMID:16170316 doi:ng1641
- ↑ Gripp KW, Lin AE, Stabley DL, Nicholson L, Scott CI Jr, Doyle D, Aoki Y, Matsubara Y, Zackai EH, Lapunzina P, Gonzalez-Meneses A, Holbrook J, Agresta CA, Gonzalez IL, Sol-Church K. HRAS mutation analysis in Costello syndrome: genotype and phenotype correlation. Am J Med Genet A. 2006 Jan 1;140(1):1-7. PMID:16329078 doi:10.1002/ajmg.a.31047
- ↑ Kerr B, Delrue MA, Sigaudy S, Perveen R, Marche M, Burgelin I, Stef M, Tang B, Eden OB, O'Sullivan J, De Sandre-Giovannoli A, Reardon W, Brewer C, Bennett C, Quarell O, M'Cann E, Donnai D, Stewart F, Hennekam R, Cave H, Verloes A, Philip N, Lacombe D, Levy N, Arveiler B, Black G. Genotype-phenotype correlation in Costello syndrome: HRAS mutation analysis in 43 cases. J Med Genet. 2006 May;43(5):401-5. Epub 2006 Jan 27. PMID:16443854 doi:jmg.2005.040352
- ↑ Zampino G, Pantaleoni F, Carta C, Cobellis G, Vasta I, Neri C, Pogna EA, De Feo E, Delogu A, Sarkozy A, Atzeri F, Selicorni A, Rauen KA, Cytrynbaum CS, Weksberg R, Dallapiccola B, Ballabio A, Gelb BD, Neri G, Tartaglia M. Diversity, parental germline origin, and phenotypic spectrum of de novo HRAS missense changes in Costello syndrome. Hum Mutat. 2007 Mar;28(3):265-72. PMID:17054105 doi:10.1002/humu.20431
- ↑ Gripp KW, Innes AM, Axelrad ME, Gillan TL, Parboosingh JS, Davies C, Leonard NJ, Lapointe M, Doyle D, Catalano S, Nicholson L, Stabley DL, Sol-Church K. Costello syndrome associated with novel germline HRAS mutations: an attenuated phenotype? Am J Med Genet A. 2008 Mar 15;146A(6):683-90. PMID:18247425 doi:10.1002/ajmg.a.32227
- ↑ Lo IF, Brewer C, Shannon N, Shorto J, Tang B, Black G, Soo MT, Ng DK, Lam ST, Kerr B. Severe neonatal manifestations of Costello syndrome. J Med Genet. 2008 Mar;45(3):167-71. Epub 2007 Nov 26. PMID:18039947 doi:10.1136/jmg.2007.054411
- ↑ Gremer L, De Luca A, Merbitz-Zahradnik T, Dallapiccola B, Morlot S, Tartaglia M, Kutsche K, Ahmadian MR, Rosenberger G. Duplication of Glu37 in the switch I region of HRAS impairs effector/GAP binding and underlies Costello syndrome by promoting enhanced growth factor-dependent MAPK and AKT activation. Hum Mol Genet. 2010 Mar 1;19(5):790-802. doi: 10.1093/hmg/ddp548. Epub 2009 Dec, 8. PMID:19995790 doi:10.1093/hmg/ddp548
- ↑ van der Burgt I, Kupsky W, Stassou S, Nadroo A, Barroso C, Diem A, Kratz CP, Dvorsky R, Ahmadian MR, Zenker M. Myopathy caused by HRAS germline mutations: implications for disturbed myogenic differentiation in the presence of constitutive HRas activation. J Med Genet. 2007 Jul;44(7):459-62. Epub 2007 Apr 5. PMID:17412879 doi:jmg.2007.049270
- ↑ Sakai E, Rikimaru K, Ueda M, Matsumoto Y, Ishii N, Enomoto S, Yamamoto H, Tsuchida N. The p53 tumor-suppressor gene and ras oncogene mutations in oral squamous-cell carcinoma. Int J Cancer. 1992 Dec 2;52(6):867-72. PMID:1459726
- ↑ Groesser L, Herschberger E, Ruetten A, Ruivenkamp C, Lopriore E, Zutt M, Langmann T, Singer S, Klingseisen L, Schneider-Brachert W, Toll A, Real FX, Landthaler M, Hafner C. Postzygotic HRAS and KRAS mutations cause nevus sebaceous and Schimmelpenning syndrome. Nat Genet. 2012 Jun 10;44(7):783-7. doi: 10.1038/ng.2316. PMID:22683711 doi:10.1038/ng.2316
- ↑ Guil S, de La Iglesia N, Fernandez-Larrea J, Cifuentes D, Ferrer JC, Guinovart JJ, Bach-Elias M. Alternative splicing of the human proto-oncogene c-H-ras renders a new Ras family protein that trafficks to cytoplasm and nucleus. Cancer Res. 2003 Sep 1;63(17):5178-87. PMID:14500341
- ↑ Lander HM, Hajjar DP, Hempstead BL, Mirza UA, Chait BT, Campbell S, Quilliam LA. A molecular redox switch on p21(ras). Structural basis for the nitric oxide-p21(ras) interaction. J Biol Chem. 1997 Feb 14;272(7):4323-6. PMID:9020151
- ↑ Williams JG, Pappu K, Campbell SL. Structural and biochemical studies of p21Ras S-nitrosylation and nitric oxide-mediated guanine nucleotide exchange. Proc Natl Acad Sci U S A. 2003 May 27;100(11):6376-81. Epub 2003 May 9. PMID:12740440 doi:10.1073/pnas.1037299100
- ↑ Ito Y, Yamasaki K, Iwahara J, Terada T, Kamiya A, Shirouzu M, Muto Y, Kawai G, Yokoyama S, Laue ED, Walchli M, Shibata T, Nishimura S, Miyazawa T. Regional polysterism in the GTP-bound form of the human c-Ha-Ras protein. Biochemistry. 1997 Jul 29;36(30):9109-19. PMID:9230043 doi:http://dx.doi.org/10.1021/bi970296u
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