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2ast

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2ast, resolution 2.30Å ()
Ligands:
Non-Standard Residues:
Gene: SKP1A, EMC19, OCP2, SKP1, TCEB1L (Homo sapiens), SKP2, FBXL1 (Homo sapiens), CKS1, CKS1B (Homo sapiens)
Related: 2ass, 1fqv
Resources: FirstGlance, OCA, RCSB, PDBsum
Coordinates: save as pdb, mmCIF, xml


Contents

Crystal structure of Skp1-Skp2-Cks1 in complex with a p27 peptide

Publication Abstract from PubMed

The ubiquitin-mediated proteolysis of the Cdk2 inhibitor p27(Kip1) plays a central role in cell cycle progression, and enhanced degradation of p27(Kip1) is associated with many common cancers. Proteolysis of p27(Kip1) is triggered by Thr187 phosphorylation, which leads to the binding of the SCF(Skp2) (Skp1-Cul1-Rbx1-Skp2) ubiquitin ligase complex. Unlike other known SCF substrates, p27(Kip1) ubiquitination also requires the accessory protein Cks1. The crystal structure of the Skp1-Skp2-Cks1 complex bound to a p27(Kip1) phosphopeptide shows that Cks1 binds to the leucine-rich repeat (LRR) domain and C-terminal tail of Skp2, whereas p27(Kip1) binds to both Cks1 and Skp2. The phosphorylated Thr187 side chain of p27(Kip1) is recognized by a Cks1 phosphate binding site, whereas the side chain of an invariant Glu185 inserts into the interface between Skp2 and Cks1, interacting with both. The structure and biochemical data support the proposed model that Cdk2-cyclin A contributes to the recruitment of p27(Kip1) to the SCF(Skp2)-Cks1 complex.

Structural basis of the Cks1-dependent recognition of p27(Kip1) by the SCF(Skp2) ubiquitin ligase., Hao B, Zheng N, Schulman BA, Wu G, Miller JJ, Pagano M, Pavletich NP, Mol Cell. 2005 Oct 7;20(1):9-19. PMID:16209941

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

Disease

[CDN1B_HUMAN] Defects in CDKN1B are the cause of multiple endocrine neoplasia type 4 (MEN4) [MIM:610755]. Multiple endocrine neoplasia (MEN) syndromes are inherited cancer syndromes of the thyroid. MEN4 is a MEN-like syndrome with a phenotypic overlap of both MEN1 and MEN2.[1]

Function

[CDN1B_HUMAN] Important regulator of cell cycle progression. Involved in G1 arrest. Potent inhibitor of cyclin E- and cyclin A-CDK2 complexes. Forms a complex with cyclin type D-CDK4 complexes and is involved in the assembly, stability, and modulation of CCND1-CDK4 complex activation. Acts either as an inhibitor or an activator of cyclin type D-CDK4 complexes depending on its phosphorylation state and/or stoichometry.[2][3][4][5][6] [SKP1_HUMAN] Essential component of the SCF (SKP1-CUL1-F-box protein) ubiquitin ligase complex, which mediates the ubiquitination of proteins involved in cell cycle progression, signal transduction and transcription. In the SCF complex, serves as an adapter that links the F-box protein to CUL1. SCF(BTRC) mediates the ubiquitination of NFKBIA at 'Lys-21' and 'Lys-22'; the degradation frees the associated NFKB1-RELA dimer to translocate into the nucleus and to activate transcription. SCF(Cyclin F) directs ubiquitination of CP110.[7][8] [CKS1_HUMAN] Binds to the catalytic subunit of the cyclin dependent kinases and is essential for their biological function. [SKP2_HUMAN] Substrate recognition component of a SCF (SKP1-CUL1-F-box protein) E3 ubiquitin-protein ligase complex which mediates the ubiquitination and subsequent proteasomal degradation of target proteins involved in cell cycle progression, signal transduction and transcription. Specifically recognizes phosphorylated CDKN1B/p27kip and is involved in regulation of G1/S transition. Degradation of CDKN1B/p27kip also requires CKS1. Recognizes target proteins ORC1, CDT1, RBL2, MLL, CDK9, RAG2, FOXO1, UBP43, and probably MYC, TOB1 and TAL1. Degradation of TAL1 also requires STUB1. Recognizes CDKN1A in association with CCNE1 or CCNE2 and CDK2. Promotes ubiquitination and destruction of CDH1 in a CK1-Dependent Manner, thereby regulating cell migration.[9][10][11][12][13][14][15][16][17][18][19][20][21][22]

About this Structure

2ast is a 4 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA.

Reference

  • Hao B, Zheng N, Schulman BA, Wu G, Miller JJ, Pagano M, Pavletich NP. Structural basis of the Cks1-dependent recognition of p27(Kip1) by the SCF(Skp2) ubiquitin ligase. Mol Cell. 2005 Oct 7;20(1):9-19. PMID:16209941 doi:10.1016/j.molcel.2005.09.003
  1. Pellegata NS, Quintanilla-Martinez L, Siggelkow H, Samson E, Bink K, Hofler H, Fend F, Graw J, Atkinson MJ. Germ-line mutations in p27Kip1 cause a multiple endocrine neoplasia syndrome in rats and humans. Proc Natl Acad Sci U S A. 2006 Oct 17;103(42):15558-63. Epub 2006 Oct 9. PMID:17030811 doi:0603877103
  2. Ishida N, Kitagawa M, Hatakeyama S, Nakayama K. Phosphorylation at serine 10, a major phosphorylation site of p27(Kip1), increases its protein stability. J Biol Chem. 2000 Aug 18;275(33):25146-54. PMID:10831586 doi:10.1074/jbc.M001144200
  3. Shin I, Yakes FM, Rojo F, Shin NY, Bakin AV, Baselga J, Arteaga CL. PKB/Akt mediates cell-cycle progression by phosphorylation of p27(Kip1) at threonine 157 and modulation of its cellular localization. Nat Med. 2002 Oct;8(10):1145-52. Epub 2002 Sep 16. PMID:12244301 doi:10.1038/nm759
  4. 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
  5. Ray A, James MK, Larochelle S, Fisher RP, Blain SW. p27Kip1 inhibits cyclin D-cyclin-dependent kinase 4 by two independent modes. Mol Cell Biol. 2009 Feb;29(4):986-99. doi: 10.1128/MCB.00898-08. Epub 2008 Dec, 15. PMID:19075005 doi:10.1128/MCB.00898-08
  6. Grimmler M, Wang Y, Mund T, Cilensek Z, Keidel EM, Waddell MB, Jakel H, Kullmann M, Kriwacki RW, Hengst L. Cdk-inhibitory activity and stability of p27Kip1 are directly regulated by oncogenic tyrosine kinases. Cell. 2007 Jan 26;128(2):269-80. PMID:17254966 doi:S0092-8674(06)01645-X
  7. Hao B, Zheng N, Schulman BA, Wu G, Miller JJ, Pagano M, Pavletich NP. Structural basis of the Cks1-dependent recognition of p27(Kip1) by the SCF(Skp2) ubiquitin ligase. Mol Cell. 2005 Oct 7;20(1):9-19. PMID:16209941 doi:10.1016/j.molcel.2005.09.003
  8. Li Y, Hao B. Structural basis of dimerization-dependent ubiquitination by the SCF(Fbx4) ubiquitin ligase. J Biol Chem. 2010 Apr 30;285(18):13896-906. Epub 2010 Feb 24. PMID:20181953 doi:10.1074/jbc.M110.111518
  9. Tedesco D, Lukas J, Reed SI. The pRb-related protein p130 is regulated by phosphorylation-dependent proteolysis via the protein-ubiquitin ligase SCF(Skp2). Genes Dev. 2002 Nov 15;16(22):2946-57. PMID:12435635 doi:10.1101/gad.1011202
  10. Mendez J, Zou-Yang XH, Kim SY, Hidaka M, Tansey WP, Stillman B. Human origin recognition complex large subunit is degraded by ubiquitin-mediated proteolysis after initiation of DNA replication. Mol Cell. 2002 Mar;9(3):481-91. PMID:11931757
  11. Li X, Zhao Q, Liao R, Sun P, Wu X. The SCF(Skp2) ubiquitin ligase complex interacts with the human replication licensing factor Cdt1 and regulates Cdt1 degradation. J Biol Chem. 2003 Aug 15;278(33):30854-8. Epub 2003 Jul 2. PMID:12840033 doi:10.1074/jbc.C300251200
  12. von der Lehr N, Johansson S, Wu S, Bahram F, Castell A, Cetinkaya C, Hydbring P, Weidung I, Nakayama K, Nakayama KI, Soderberg O, Kerppola TK, Larsson LG. The F-box protein Skp2 participates in c-Myc proteosomal degradation and acts as a cofactor for c-Myc-regulated transcription. Mol Cell. 2003 May;11(5):1189-200. PMID:12769844
  13. Tokarz S, Berset C, La Rue J, Friedman K, Nakayama K, Nakayama K, Zhang DE, Lanker S. The ISG15 isopeptidase UBP43 is regulated by proteolysis via the SCFSkp2 ubiquitin ligase. J Biol Chem. 2004 Nov 5;279(45):46424-30. Epub 2004 Sep 1. PMID:15342634 doi:10.1074/jbc.M403189200
  14. Wang W, Nacusi L, Sheaff RJ, Liu X. Ubiquitination of p21Cip1/WAF1 by SCFSkp2: substrate requirement and ubiquitination site selection. Biochemistry. 2005 Nov 8;44(44):14553-64. PMID:16262255 doi:10.1021/bi051071j
  15. Jiang H, Chang FC, Ross AE, Lee J, Nakayama K, Nakayama K, Desiderio S. Ubiquitylation of RAG-2 by Skp2-SCF links destruction of the V(D)J recombinase to the cell cycle. Mol Cell. 2005 Jun 10;18(6):699-709. PMID:15949444 doi:S1097-2765(05)01317-1
  16. Barboric M, Zhang F, Besenicar M, Plemenitas A, Peterlin BM. Ubiquitylation of Cdk9 by Skp2 facilitates optimal Tat transactivation. J Virol. 2005 Sep;79(17):11135-41. PMID:16103164 doi:79/17/11135
  17. Huang H, Regan KM, Wang F, Wang D, Smith DI, van Deursen JM, Tindall DJ. Skp2 inhibits FOXO1 in tumor suppression through ubiquitin-mediated degradation. Proc Natl Acad Sci U S A. 2005 Feb 1;102(5):1649-54. Epub 2005 Jan 24. PMID:15668399 doi:10.1073/pnas.0406789102
  18. Hiramatsu Y, Kitagawa K, Suzuki T, Uchida C, Hattori T, Kikuchi H, Oda T, Hatakeyama S, Nakayama KI, Yamamoto T, Konno H, Kitagawa M. Degradation of Tob1 mediated by SCFSkp2-dependent ubiquitination. Cancer Res. 2006 Sep 1;66(17):8477-83. PMID:16951159 doi:66/17/8477
  19. Liu Y, Hedvat CV, Mao S, Zhu XH, Yao J, Nguyen H, Koff A, Nimer SD. The ETS protein MEF is regulated by phosphorylation-dependent proteolysis via the protein-ubiquitin ligase SCFSkp2. Mol Cell Biol. 2006 Apr;26(8):3114-23. PMID:16581786 doi:10.1128/MCB.26.8.3114-3123.2006
  20. Liu H, Cheng EH, Hsieh JJ. Bimodal degradation of MLL by SCFSkp2 and APCCdc20 assures cell cycle execution: a critical regulatory circuit lost in leukemogenic MLL fusions. Genes Dev. 2007 Oct 1;21(19):2385-98. PMID:17908926 doi:21/19/2385
  21. Nie L, Wu H, Sun XH. Ubiquitination and degradation of Tal1/SCL are induced by notch signaling and depend on Skp2 and CHIP. J Biol Chem. 2008 Jan 11;283(2):684-92. Epub 2007 Oct 25. PMID:17962192 doi:10.1074/jbc.M704981200
  22. Inuzuka H, Gao D, Finley LW, Yang W, Wan L, Fukushima H, Chin YR, Zhai B, Shaik S, Lau AW, Wang Z, Gygi SP, Nakayama K, Teruya-Feldstein J, Toker A, Haigis MC, Pandolfi PP, Wei W. Acetylation-dependent regulation of Skp2 function. Cell. 2012 Jul 6;150(1):179-93. doi: 10.1016/j.cell.2012.05.038. PMID:22770219 doi:10.1016/j.cell.2012.05.038

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