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==MECHANISM OF G1 CYCLIN DEPENDENT KINASE INHIBITION FROM THE STRUCTURE OF THE CDK6-P16INK4A TUMOR SUPPRESSOR COMPLEX==
==MECHANISM OF G1 CYCLIN DEPENDENT KINASE INHIBITION FROM THE STRUCTURE OF THE CDK6-P16INK4A TUMOR SUPPRESSOR COMPLEX==
<StructureSection load='1bi7' size='340' side='right' caption='[[1bi7]], [[Resolution|resolution]] 3.40&Aring;' scene=''>
<StructureSection load='1bi7' size='340' side='right' caption='[[1bi7]], [[Resolution|resolution]] 3.40&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
<table><tr><td colspan='2'>[[1bi7]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1BI7 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=1BI7 FirstGlance]. <br>
<table><tr><td colspan='2'>[[1bi7]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1BI7 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=1BI7 FirstGlance]. <br>
</td></tr><tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=1bi7 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1bi7 OCA], [http://pdbe.org/1bi7 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=1bi7 RCSB], [http://www.ebi.ac.uk/pdbsum/1bi7 PDBsum]</span></td></tr>
</td></tr><tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=1bi7 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1bi7 OCA], [http://pdbe.org/1bi7 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=1bi7 RCSB], [http://www.ebi.ac.uk/pdbsum/1bi7 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=1bi7 ProSAT]</span></td></tr>
</table>
</table>
== Disease ==
== Disease ==
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</div>
</div>
<div class="pdbe-citations 1bi7" style="background-color:#fffaf0;"></div>
<div class="pdbe-citations 1bi7" style="background-color:#fffaf0;"></div>
==See Also==
*[[Cyclin-dependent kinase|Cyclin-dependent kinase]]
== References ==
== References ==
<references/>
<references/>

Revision as of 14:09, 22 November 2017

MECHANISM OF G1 CYCLIN DEPENDENT KINASE INHIBITION FROM THE STRUCTURE OF THE CDK6-P16INK4A TUMOR SUPPRESSOR COMPLEXMECHANISM OF G1 CYCLIN DEPENDENT KINASE INHIBITION FROM THE STRUCTURE OF THE CDK6-P16INK4A TUMOR SUPPRESSOR COMPLEX

Structural highlights

1bi7 is a 2 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

[CD2A1_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

[CDK6_HUMAN] Serine/threonine-protein kinase involved in the control of the cell cycle and differentiation; promotes G1/S transition. Phosphorylates pRB/RB1 and NPM1. Interacts with D-type G1 cyclins during interphase at G1 to form a pRB/RB1 kinase and controls the entrance into the cell cycle. Involved in initiation and maintenance of cell cycle exit during cell differentiation; prevents cell proliferation and regulates negatively cell differentiation, but is required for the proliferation of specific cell types (e.g. erythroid and hematopoietic cells). Essential for cell proliferation within the dentate gyrus of the hippocampus and the subventricular zone of the lateral ventricles. Required during thymocyte development. Promotes the production of newborn neurons, probably by modulating G1 length. Promotes, at least in astrocytes, changes in patterns of gene expression, changes in the actin cytoskeleton including loss of stress fibers, and enhanced motility during cell differentiation. Prevents myeloid differentiation by interfering with RUNX1 and reducing its transcription transactivation activity, but promotes proliferation of normal myeloid progenitors. Delays senescence. Promotes the proliferation of beta-cells in pancreatic islets of Langerhans.[15] [16] [17] [18] [19] [20] [21] [22] [23] [CD2A1_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.[24] [25]

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 cyclin-dependent kinases 4 and 6 (Cdk4/6) that control the G1 phase of the cell cycle and their inhibitor, the p16INK4a tumour suppressor, have a central role in cell proliferation and in tumorigenesis. The structures of Cdk6 bound to p16INK4a and to the related p19INK4d reveal that the INK4 inhibitors bind next to the ATP-binding site of the catalytic cleft, opposite where the activating cyclin subunit binds. They prevent cyclin binding indirectly by causing structural changes that propagate to the cyclin-binding site. The INK4 inhibitors also distort the kinase catalytic cleft and interfere with ATP binding, which explains how they can inhibit the preassembled Cdk4/6-cyclin D complexes as well. Tumour-derived mutations in INK4a and Cdk4 map to interface contacts, solidifying the role of CDK binding and inhibition in the tumour suppressor activity of p16INK4a.

Structural basis for inhibition of the cyclin-dependent kinase Cdk6 by the tumour suppressor p16INK4a.,Russo AA, Tong L, Lee JO, Jeffrey PD, Pavletich NP Nature. 1998 Sep 17;395(6699):237-43. PMID:9751050[26]

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. ↑ Meyerson M, Harlow E. Identification of G1 kinase activity for cdk6, a novel cyclin D partner. Mol Cell Biol. 1994 Mar;14(3):2077-86. PMID:8114739
  16. ↑ Matushansky I, Radparvar F, Skoultchi AI. CDK6 blocks differentiation: coupling cell proliferation to the block to differentiation in leukemic cells. Oncogene. 2003 Jul 3;22(27):4143-9. PMID:12833137 doi:10.1038/sj.onc.1206484
  17. ↑ Lucas JJ, Domenico J, Gelfand EW. Cyclin-dependent kinase 6 inhibits proliferation of human mammary epithelial cells. Mol Cancer Res. 2004 Feb;2(2):105-14. PMID:14985467
  18. ↑ Ogasawara T, Kawaguchi H, Jinno S, Hoshi K, Itaka K, Takato T, Nakamura K, Okayama H. Bone morphogenetic protein 2-induced osteoblast differentiation requires Smad-mediated down-regulation of Cdk6. Mol Cell Biol. 2004 Aug;24(15):6560-8. PMID:15254224 doi:10.1128/MCB.24.15.6560-6568.2004
  19. ↑ Takaki T, Fukasawa K, Suzuki-Takahashi I, Semba K, Kitagawa M, Taya Y, Hirai H. Preferences for phosphorylation sites in the retinoblastoma protein of D-type cyclin-dependent kinases, Cdk4 and Cdk6, in vitro. J Biochem. 2005 Mar;137(3):381-6. PMID:15809340 doi:10.1093/jb/mvi050
  20. ↑ Fujimoto T, Anderson K, Jacobsen SE, Nishikawa SI, Nerlov C. Cdk6 blocks myeloid differentiation by interfering with Runx1 DNA binding and Runx1-C/EBPalpha interaction. EMBO J. 2007 May 2;26(9):2361-70. Epub 2007 Apr 12. PMID:17431401 doi:10.1038/sj.emboj.7601675
  21. ↑ Ruas M, Gregory F, Jones R, Poolman R, Starborg M, Rowe J, Brookes S, Peters G. CDK4 and CDK6 delay senescence by kinase-dependent and p16INK4a-independent mechanisms. Mol Cell Biol. 2007 Jun;27(12):4273-82. Epub 2007 Apr 9. PMID:17420273 doi:10.1128/MCB.02286-06
  22. ↑ Fiaschi-Taesch NM, Salim F, Kleinberger J, Troxell R, Cozar-Castellano I, Selk K, Cherok E, Takane KK, Scott DK, Stewart AF. Induction of human beta-cell proliferation and engraftment using a single G1/S regulatory molecule, cdk6. Diabetes. 2010 Aug;59(8):1926-36. doi: 10.2337/db09-1776. PMID:20668294 doi:10.2337/db09-1776
  23. ↑ Sarek G, Jarviluoma A, Moore HM, Tojkander S, Vartia S, Biberfeld P, Laiho M, Ojala PM. Nucleophosmin phosphorylation by v-cyclin-CDK6 controls KSHV latency. PLoS Pathog. 2010 Mar 19;6(3):e1000818. doi: 10.1371/journal.ppat.1000818. PMID:20333249 doi:10.1371/journal.ppat.1000818
  24. ↑ 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
  25. ↑ 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
  26. ↑ Russo AA, Tong L, Lee JO, Jeffrey PD, Pavletich NP. Structural basis for inhibition of the cyclin-dependent kinase Cdk6 by the tumour suppressor p16INK4a. Nature. 1998 Sep 17;395(6699):237-43. PMID:9751050 doi:http://dx.doi.org/10.1038/26155

1bi7, resolution 3.40Å

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