2a5e is a 1 chain structure with sequence from Homo sapiens. Full experimental information is available from OCA. For a guided tour on the structure components use FirstGlance.
CDN2A_HUMAN Note=The association between cutaneous and uveal melanomas in some families suggests that mutations in CDKN2A may account for a proportion of uveal melanomas. However, CDKN2A mutations are rarely found in uveal melanoma patients. Defects in CDKN2A are the cause of cutaneous malignant melanoma type 2 (CMM2) [MIM:155601. Malignant melanoma is a malignant neoplasm of melanocytes, arising de novo or from a pre-existing benign nevus, which occurs most often in the skin but also may involve other sites.[1][2][3][4][5][6][7][8][9][10][11][12] Defects in CDKN2A are the cause of familial atypical multiple mole melanoma-pancreatic carcinoma syndrome (FAMMMPC) [MIM:606719. Defects in CDKN2A are a cause of Li-Fraumeni syndrome (LFS) [MIM:151623. LFS is a highly penetrant familial cancer phenotype usually associated with inherited mutations in TP53.[13] Defects in CDKN2A are the cause of melanoma-astrocytoma syndrome (MASTS) [MIM:155755. The melanoma-astrocytoma syndrome is characterized by a dual predisposition to melanoma and neural system tumors, commonly astrocytoma.[14]
Function
CDN2A_HUMAN Acts as a negative regulator of the proliferation of normal cells by interacting strongly with CDK4 and CDK6. This inhibits their ability to interact with cyclins D and to phosphorylate the retinoblastoma protein.[15][16]
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 solution structure of the tumor suppressor p16INK4A has been determined by NMR, and important recognition regions of both cdk4 and p16INK4A have been identified. The tertiary structure of p16INK4A contains four helix-turn-helix motifs linked by three loops. Twelve tumorigenic mutants of p16INK4A have been constructed and analyzed for their structure and activity, and new mutants have been designed rationally. A fragment of 58 residues at the N terminus of cdk4 important for p16INK4A binding has been identified. The importance of this region was further verified by mutational analysis of cdk4. These results and docking experiments have been used to assess possible modes of binding between p16INK4A and cdk4.
Tumor suppressor p16INK4A: determination of solution structure and analyses of its interaction with cyclin-dependent kinase 4.,Byeon IJ, Li J, Ericson K, Selby TL, Tevelev A, Kim HJ, O'Maille P, Tsai MD Mol Cell. 1998 Feb;1(3):421-31. PMID:9660926[17]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
↑Walker GJ, Hussussian CJ, Flores JF, Glendening JM, Haluska FG, Dracopoli NC, Hayward NK, Fountain JW. Mutations of the CDKN2/p16INK4 gene in Australian melanoma kindreds. Hum Mol Genet. 1995 Oct;4(10):1845-52. PMID:8595405
↑Borg A, Johannsson U, Johannsson O, Hakansson S, Westerdahl J, Masback A, Olsson H, Ingvar C. Novel germline p16 mutation in familial malignant melanoma in southern Sweden. Cancer Res. 1996 Jun 1;56(11):2497-500. PMID:8653684
↑FitzGerald MG, Harkin DP, Silva-Arrieta S, MacDonald DJ, Lucchina LC, Unsal H, O'Neill E, Koh J, Finkelstein DM, Isselbacher KJ, Sober AJ, Haber DA. Prevalence of germ-line mutations in p16, p19ARF, and CDK4 in familial melanoma: analysis of a clinic-based population. Proc Natl Acad Sci U S A. 1996 Aug 6;93(16):8541-5. PMID:8710906
↑Harland M, Meloni R, Gruis N, Pinney E, Brookes S, Spurr NK, Frischauf AM, Bataille V, Peters G, Cuzick J, Selby P, Bishop DT, Bishop JN. Germline mutations of the CDKN2 gene in UK melanoma families. Hum Mol Genet. 1997 Nov;6(12):2061-7. PMID:9328469
↑Soufir N, Avril MF, Chompret A, Demenais F, Bombled J, Spatz A, Stoppa-Lyonnet D, Benard J, Bressac-de Paillerets B. Prevalence of p16 and CDK4 germline mutations in 48 melanoma-prone families in France. The French Familial Melanoma Study Group. Hum Mol Genet. 1998 Feb;7(2):209-16. PMID:9425228
↑Gretarsdottir S, Olafsdottir GH, Borg A. Five novel somatic CDKN2/p16 mutations identified in melanoma, glioma and carcinoma of the pancreas. Mutations in brief no. 170. Online. Hum Mutat. 1998;12(3):212. PMID:10651484
↑Goldstein AM, Liu L, Shennan MG, Hogg D, Tucker MA, Struewing JP. A common founder for the V126D CDKN2A mutation in seven North American melanoma-prone families. Br J Cancer. 2001 Aug 17;85(4):527-30. PMID:11506491 doi:10.1054/bjoc.2001.1944
↑Hewitt C, Lee Wu C, Evans G, Howell A, Elles RG, Jordan R, Sloan P, Read AP, Thakker N. Germline mutation of ARF in a melanoma kindred. Hum Mol Genet. 2002 May 15;11(11):1273-9. PMID:12019208
↑Ruiz A, Puig S, Malvehy J, Lazaro C, Lynch M, Gimenez-Arnau AM, Puig L, Sanchez-Conejo J, Estivill X, Castel T. CDKN2A mutations in Spanish cutaneous malignant melanoma families and patients with multiple melanomas and other neoplasia. J Med Genet. 1999 Jun;36(6):490-3. PMID:10874641
↑Avbelj M, Hocevar M, Trebusak-Podkrajsek K, Krzisnik C, Battelino T. A novel L94Q mutation in the CDKN2A gene in a melanoma kindred. Melanoma Res. 2003 Dec;13(6):567-70. PMID:14646619 doi:10.1097/01.cmr.0000056289.15046.c0
↑Kannengiesser C, Brookes S, del Arroyo AG, Pham D, Bombled J, Barrois M, Mauffret O, Avril MF, Chompret A, Lenoir GM, Sarasin A, Peters G, Bressac-de Paillerets B. Functional, structural, and genetic evaluation of 20 CDKN2A germ line mutations identified in melanoma-prone families or patients. Hum Mutat. 2009 Apr;30(4):564-74. doi: 10.1002/humu.20845. PMID:19260062 doi:10.1002/humu.20845
↑Guran S, Tunca Y, Imirzalioglu N. Hereditary TP53 codon 292 and somatic P16INK4A codon 94 mutations in a Li-Fraumeni syndrome family. Cancer Genet Cytogenet. 1999 Sep;113(2):145-51. PMID:10484981
↑Randerson-Moor JA, Harland M, Williams S, Cuthbert-Heavens D, Sheridan E, Aveyard J, Sibley K, Whitaker L, Knowles M, Bishop JN, Bishop DT. A germline deletion of p14(ARF) but not CDKN2A in a melanoma-neural system tumour syndrome family. Hum Mol Genet. 2001 Jan 1;10(1):55-62. PMID:11136714
↑Okamoto A, Demetrick DJ, Spillare EA, Hagiwara K, Hussain SP, Bennett WP, Forrester K, Gerwin B, Serrano M, Beach DH, et al.. Mutations and altered expression of p16INK4 in human cancer. Proc Natl Acad Sci U S A. 1994 Nov 8;91(23):11045-9. PMID:7972006
↑Bockstaele L, Kooken H, Libert F, Paternot S, Dumont JE, de Launoit Y, Roger PP, Coulonval K. Regulated activating Thr172 phosphorylation of cyclin-dependent kinase 4(CDK4): its relationship with cyclins and CDK "inhibitors". Mol Cell Biol. 2006 Jul;26(13):5070-85. PMID:16782892 doi:10.1128/MCB.02006-05
↑Byeon IJ, Li J, Ericson K, Selby TL, Tevelev A, Kim HJ, O'Maille P, Tsai MD. Tumor suppressor p16INK4A: determination of solution structure and analyses of its interaction with cyclin-dependent kinase 4. Mol Cell. 1998 Feb;1(3):421-31. PMID:9660926
