Proteopedia

8cdk

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CAND1 b-hairpin++-SCF-SKP2 CAND1 partly engaged SCF partly rockedCAND1 b-hairpin++-SCF-SKP2 CAND1 partly engaged SCF partly rocked

Structural highlights

8cdk is a 5 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

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.[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14]

Publication Abstract from PubMed

Cells respond to environmental cues by remodeling their inventories of multiprotein complexes. Cellular repertoires of SCF (SKP1-CUL1-F box protein) ubiquitin ligase complexes, which mediate much protein degradation, require CAND1 to distribute the limiting CUL1 subunit across the family of approximately 70 different F box proteins. Yet, how a single factor coordinately assembles numerous distinct multiprotein complexes remains unknown. We obtained cryo-EM structures of CAND1-bound SCF complexes in multiple states and correlated mutational effects on structures, biochemistry, and cellular assays. The data suggest that CAND1 clasps idling catalytic domains of an inactive SCF, rolls around, and allosterically rocks and destabilizes the SCF. New SCF production proceeds in reverse, through SKP1-F box allosterically destabilizing CAND1. The CAND1-SCF conformational ensemble recycles CUL1 from inactive complexes, fueling mixing and matching of SCF parts for E3 activation in response to substrate availability. Our data reveal biogenesis of a predominant family of E3 ligases, and the molecular basis for systemwide multiprotein complex assembly.

Systemwide disassembly and assembly of SCF ubiquitin ligase complexes.,Baek K, Scott DC, Henneberg LT, King MT, Mann M, Schulman BA Cell. 2023 Mar 31:S0092-8674(23)00213-1. doi: 10.1016/j.cell.2023.02.035. PMID:37028429[15]

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

References

  1. ↑ 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
  2. ↑ 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
  3. ↑ 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
  4. ↑ 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
  5. ↑ 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
  6. ↑ 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
  7. ↑ 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
  8. ↑ 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
  9. ↑ 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
  10. ↑ 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
  11. ↑ 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
  12. ↑ 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
  13. ↑ 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
  14. ↑ 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
  15. ↑ Baek K, Scott DC, Henneberg LT, King MT, Mann M, Schulman BA. Systemwide disassembly and assembly of SCF ubiquitin ligase complexes. Cell. 2023 Mar 31:S0092-8674(23)00213-1. PMID:37028429 doi:10.1016/j.cell.2023.02.035

8cdk, resolution 3.32Å

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