1dc2

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SOLUTION NMR STRUCTURE OF TUMOR SUPPRESSOR P16INK4A, 20 STRUCTURESSOLUTION NMR STRUCTURE OF TUMOR SUPPRESSOR P16INK4A, 20 STRUCTURES

Structural highlights

1dc2 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.
Method:Solution NMR
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

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

Within the tumor suppressor protein INK4 (inhibitor of cyclin-dependent kinase 4) family, p15INK4B is the smallest and the only one whose structure has not been determined previously, probably due to the protein's conformational flexibility and instability. In this work, multidimensional NMR studies were performed on this protein. The first tertiary structure was built by comparative modeling with p16INK4A as the template, followed by restrained energy minimization with NMR constraints (NOE and H-bonds). For this purpose, the solution structure of pl6INK4A, whose quality was also limited by similar problems, was refined with additional NMR experiments conducted on an 800 MHz spectrometer and by structure-based iterative NOE assignments. The nonhelical regions showed major improvement with root-mean-square deviation (RMSD) improved from 1.23 to 0.68 A for backbone heavy atoms. The completion of p15INK4B coupled with refinement of p16INK4A made it possible to compare the structures of the four INK4 members in depth, and to compare the structures of p16INK4A in the free form and in the p16INK4A-CDK6 complex. This is an important step toward a comprehensive understanding of the precise functional roles of each INK4 member.

Tumor suppressor INK4: refinement of p16INK4A structure and determination of p15INK4B structure by comparative modeling and NMR data.,Yuan C, Selby TL, Li J, Byeon IJ, Tsai MD Protein Sci. 2000 Jun;9(6):1120-8. PMID:10892805[17]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

  1. ↑ Hussussian CJ, Struewing JP, Goldstein AM, Higgins PA, Ally DS, Sheahan MD, Clark WH Jr, Tucker MA, Dracopoli NC. Germline p16 mutations in familial melanoma. Nat Genet. 1994 Sep;8(1):15-21. PMID:7987387 doi:http://dx.doi.org/10.1038/ng0994-15
  2. ↑ 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
  3. ↑ 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
  4. ↑ 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
  5. ↑ 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
  6. ↑ 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
  7. ↑ 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
  8. ↑ 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
  9. ↑ 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
  10. ↑ 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
  11. ↑ 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
  12. ↑ 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
  13. ↑ 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
  14. ↑ 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
  15. ↑ 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
  16. ↑ 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
  17. ↑ Yuan C, Selby TL, Li J, Byeon IJ, Tsai MD. Tumor suppressor INK4: refinement of p16INK4A structure and determination of p15INK4B structure by comparative modeling and NMR data. Protein Sci. 2000 Jun;9(6):1120-8. PMID:10892805
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