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| - | [[Image:1bi7.gif|left|200px]]<br /> | |
| - | <applet load="1bi7" size="450" color="white" frame="true" align="right" spinBox="true" | |
| - | caption="1bi7, resolution 3.4Å" /> | |
| - | '''MECHANISM OF G1 CYCLIN DEPENDENT KINASE INHIBITION FROM THE STRUCTURE OF THE CDK6-P16INK4A TUMOR SUPPRESSOR COMPLEX'''<br /> | |
| | | | |
| - | ==Overview== | + | ==MECHANISM OF G1 CYCLIN DEPENDENT KINASE INHIBITION FROM THE STRUCTURE OF THE CDK6-P16INK4A TUMOR SUPPRESSOR COMPLEX== |
| - | 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.
| + | <StructureSection load='1bi7' size='340' side='right'caption='[[1bi7]], [[Resolution|resolution]] 3.40Å' scene=''> |
| | + | == Structural highlights == |
| | + | <table><tr><td colspan='2'>[[1bi7]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. 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 [https://proteopedia.org/fgij/fg.htm?mol=1BI7 FirstGlance]. <br> |
| | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 3.4Å</td></tr> |
| | + | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=1bi7 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1bi7 OCA], [https://pdbe.org/1bi7 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1bi7 RCSB], [https://www.ebi.ac.uk/pdbsum/1bi7 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1bi7 ProSAT]</span></td></tr> |
| | + | </table> |
| | + | == Function == |
| | + | [https://www.uniprot.org/uniprot/CDK6_HUMAN 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.<ref>PMID:8114739</ref> <ref>PMID:12833137</ref> <ref>PMID:14985467</ref> <ref>PMID:15254224</ref> <ref>PMID:15809340</ref> <ref>PMID:17431401</ref> <ref>PMID:17420273</ref> <ref>PMID:20668294</ref> <ref>PMID:20333249</ref> |
| | + | == Evolutionary Conservation == |
| | + | [[Image:Consurf_key_small.gif|200px|right]] |
| | + | Check<jmol> |
| | + | <jmolCheckbox> |
| | + | <scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/bi/1bi7_consurf.spt"</scriptWhenChecked> |
| | + | <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked> |
| | + | <text>to colour the structure by Evolutionary Conservation</text> |
| | + | </jmolCheckbox> |
| | + | </jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/main_output.php?pdb_ID=1bi7 ConSurf]. |
| | + | <div style="clear:both"></div> |
| | | | |
| - | ==Disease== | + | ==See Also== |
| - | Known diseases associated with this structure: Li Fraumeni syndrome OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=600160 600160]], Melanoma and neural system tumor syndrome OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=600160 600160]], Melanoma, cutaneous malignant, 2 OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=600160 600160]], Orolaryngeal cancer, multiple, OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=600160 600160]], Pancreatic cancer/melanoma syndrome OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=600160 600160]]
| + | *[[Cyclin-dependent kinase 3D structures|Cyclin-dependent kinase 3D structures]] |
| - | | + | == References == |
| - | ==About this Structure== | + | <references/> |
| - | 1BI7 is a [http://en.wikipedia.org/wiki/Protein_complex Protein complex] structure of sequences from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://ispc.weizmann.ac.il/oca-bin/ocashort?id=1BI7 OCA].
| + | __TOC__ |
| - | | + | </StructureSection> |
| - | ==Reference==
| + | |
| - | 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:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=9751050 9751050]
| + | |
| | [[Category: Homo sapiens]] | | [[Category: Homo sapiens]] |
| - | [[Category: Protein complex]] | + | [[Category: Large Structures]] |
| - | [[Category: Jeffrey, P.D.]] | + | [[Category: Jeffrey PD]] |
| - | [[Category: Lee, J.O.]] | + | [[Category: Lee JO]] |
| - | [[Category: Pavletich, N.P.]] | + | [[Category: Pavletich NP]] |
| - | [[Category: Russo, A.A.]] | + | [[Category: Russo AA]] |
| - | [[Category: Tong, L.]] | + | [[Category: Tong L]] |
| - | [[Category: cdk]]
| + | |
| - | [[Category: cell cycle]]
| + | |
| - | [[Category: complex (kinase/anti-oncogene)]]
| + | |
| - | [[Category: cyclin dependent kinase]]
| + | |
| - | [[Category: cyclin dependent kinase inhibitory protein]]
| + | |
| - | [[Category: ink4]]
| + | |
| - | [[Category: mts1]]
| + | |
| - | [[Category: multiple tumor suppressor]]
| + | |
| - | | + | |
| - | ''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Mon Nov 12 16:10:09 2007''
| + | |
| Structural highlights
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.[1] [2] [3] [4] [5] [6] [7] [8] [9]
Evolutionary Conservation
Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.
See Also
References
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ 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
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