| Structural highlights
3mks is a 4 chain structure with sequence from Saccharomyces cerevisiae. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
| | Ligands: | , , |
| Related: | 1nex |
| Gene: | SKP1, CBF3D, YDR328C, D9798.14 (Saccharomyces cerevisiae), CDC4, YFL009W (Saccharomyces cerevisiae) |
| Resources: | FirstGlance, OCA, RCSB, PDBsum |
Function
[SKP1_YEAST] Essential component of the E3 ubiquitin ligase complex SCF (SKP1-CUL1-F-box protein) ubiquitin ligase complex, which mediates the ubiquitination and subsequent proteasomal degradation of target proteins like phosphorylated SIC1. Participates in the attachment of chromosomes to the spindle. Acts as a regulatory component of the centromere DNA-binding protein complex CBF3, which is essential for chromosome segregation and movement of centromeres along microtubules. CBF3 is required for the recruitment of other kinetochore complexes to CEN DNA. It plays a role in the attachment of chromosomes to the spindle and binds selectively to a highly conserved DNA sequence called CDEIII, found in centromeres and in several promoters. The association of CBF3C with CBF3D and SGT1 is required for CBF3C activation and CBF3 assembly. SKP1/CBF3D could retrieve cyclins or cyclin-CDK-like proteins into the kinetochore thus providing cell cycle-regulated kinetochore activity. Involved in the regulation of methionine biosynthesis genes. Facilitates association of CDC53 with CDC4 and of ROY1 with YPT52.[1] [2] [3] [4] [5] [6] [7] [CDC4_YEAST] 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. Recognizes and binds to phosphorylated target proteins. Directs ubiquitination of the phosphorylated CDK inhibitor SIC1. Involved in the degradation of CDC6 together with CDC34/UBC3 and CDC53, and in restricting the degradation of FAR1 to the nucleus. Is essential for initiation of DNA replication and separation of the spindle pole bodies to form the poles of the mitotic spindle. It also plays a role in bud development, fusion of zygotic nuclei after conjugation and various aspects of sporulation. Required for HTA1-HTB1 locus transcription activation. Required for G1/S and G2/M transition.[8] [9] [10] [11] [12] [13] [14] [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
The specificity of SCF ubiquitin ligase-mediated protein degradation is determined by F-box proteins. We identified a biplanar dicarboxylic acid compound, called SCF-I2, as an inhibitor of substrate recognition by the yeast F-box protein Cdc4 using a fluorescence polarization screen to monitor the displacement of a fluorescein-labeled phosphodegron peptide. SCF-I2 inhibits the binding and ubiquitination of full-length phosphorylated substrates by SCF(Cdc4). A co-crystal structure reveals that SCF-I2 inserts itself between the beta-strands of blades 5 and 6 of the WD40 propeller domain of Cdc4 at a site that is 25 A away from the substrate binding site. Long-range transmission of SCF-I2 interactions distorts the substrate binding pocket and impedes recognition of key determinants in the Cdc4 phosphodegron. Mutation of the SCF-I2 binding site abrogates its inhibitory effect and explains specificity in the allosteric inhibition mechanism. Mammalian WD40 domain proteins may exhibit similar allosteric responsiveness and hence represent an extensive class of druggable target.
An allosteric inhibitor of substrate recognition by the SCF(Cdc4) ubiquitin ligase.,Orlicky S, Tang X, Neduva V, Elowe N, Brown ED, Sicheri F, Tyers M Nat Biotechnol. 2010 Jul;28(7):733-7. Epub 2010 Jun 27. PMID:20581844[17]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Connelly C, Hieter P. Budding yeast SKP1 encodes an evolutionarily conserved kinetochore protein required for cell cycle progression. Cell. 1996 Jul 26;86(2):275-85. PMID:8706132
- ↑ Bai C, Sen P, Hofmann K, Ma L, Goebl M, Harper JW, Elledge SJ. SKP1 connects cell cycle regulators to the ubiquitin proteolysis machinery through a novel motif, the F-box. Cell. 1996 Jul 26;86(2):263-74. PMID:8706131
- ↑ Skowyra D, Craig KL, Tyers M, Elledge SJ, Harper JW. F-box proteins are receptors that recruit phosphorylated substrates to the SCF ubiquitin-ligase complex. Cell. 1997 Oct 17;91(2):209-19. PMID:9346238
- ↑ Feldman RM, Correll CC, Kaplan KB, Deshaies RJ. A complex of Cdc4p, Skp1p, and Cdc53p/cullin catalyzes ubiquitination of the phosphorylated CDK inhibitor Sic1p. Cell. 1997 Oct 17;91(2):221-30. PMID:9346239
- ↑ Liu Y, Nakatsukasa K, Kotera M, Kanada A, Nishimura T, Kishi T, Mimura S, Kamura T. Non-SCF-type F-box protein Roy1/Ymr258c interacts with a Rab5-like GTPase Ypt52 and inhibits Ypt52 function. Mol Biol Cell. 2011 May;22(9):1575-84. doi: 10.1091/mbc.E10-08-0716. Epub 2011, Mar 9. PMID:21389113 doi:10.1091/mbc.E10-08-0716
- ↑ Patton EE, Willems AR, Sa D, Kuras L, Thomas D, Craig KL, Tyers M. Cdc53 is a scaffold protein for multiple Cdc34/Skp1/F-box proteincomplexes that regulate cell division and methionine biosynthesis in yeast. Genes Dev. 1998 Mar 1;12(5):692-705. PMID:9499404
- ↑ Escusa S, Laporte D, Massoni A, Boucherie H, Dautant A, Daignan-Fornier B. Skp1-Cullin-F-box-dependent degradation of Aah1p requires its interaction with the F-box protein Saf1p. J Biol Chem. 2007 Jul 13;282(28):20097-103. Epub 2007 May 21. PMID:17517885 doi:10.1074/jbc.M702425200
- ↑ Kornitzer D, Raboy B, Kulka RG, Fink GR. Regulated degradation of the transcription factor Gcn4. EMBO J. 1994 Dec 15;13(24):6021-30. PMID:7813440
- ↑ Skowyra D, Craig KL, Tyers M, Elledge SJ, Harper JW. F-box proteins are receptors that recruit phosphorylated substrates to the SCF ubiquitin-ligase complex. Cell. 1997 Oct 17;91(2):209-19. PMID:9346238
- ↑ Feldman RM, Correll CC, Kaplan KB, Deshaies RJ. A complex of Cdc4p, Skp1p, and Cdc53p/cullin catalyzes ubiquitination of the phosphorylated CDK inhibitor Sic1p. Cell. 1997 Oct 17;91(2):221-30. PMID:9346239
- ↑ Li FN, Johnston M. Grr1 of Saccharomyces cerevisiae is connected to the ubiquitin proteolysis machinery through Skp1: coupling glucose sensing to gene expression and the cell cycle. EMBO J. 1997 Sep 15;16(18):5629-38. PMID:9312022 doi:10.1093/emboj/16.18.5629
- ↑ Drury LS, Perkins G, Diffley JF. The Cdc4/34/53 pathway targets Cdc6p for proteolysis in budding yeast. EMBO J. 1997 Oct 1;16(19):5966-76. PMID:9312054 doi:10.1093/emboj/16.19.5966
- ↑ Jaquenoud M, Gulli MP, Peter K, Peter M. The Cdc42p effector Gic2p is targeted for ubiquitin-dependent degradation by the SCFGrr1 complex. EMBO J. 1998 Sep 15;17(18):5360-73. PMID:9736614 doi:10.1093/emboj/17.18.5360
- ↑ Goh PY, Surana U. Cdc4, a protein required for the onset of S phase, serves an essential function during G(2)/M transition in Saccharomyces cerevisiae. Mol Cell Biol. 1999 Aug;19(8):5512-22. PMID:10409741
- ↑ Skowyra D, Koepp DM, Kamura T, Conrad MN, Conaway RC, Conaway JW, Elledge SJ, Harper JW. Reconstitution of G1 cyclin ubiquitination with complexes containing SCFGrr1 and Rbx1. Science. 1999 Apr 23;284(5414):662-5. PMID:10213692
- ↑ Blondel M, Galan JM, Chi Y, Lafourcade C, Longaretti C, Deshaies RJ, Peter M. Nuclear-specific degradation of Far1 is controlled by the localization of the F-box protein Cdc4. EMBO J. 2000 Nov 15;19(22):6085-97. PMID:11080155 doi:10.1093/emboj/19.22.6085
- ↑ Orlicky S, Tang X, Neduva V, Elowe N, Brown ED, Sicheri F, Tyers M. An allosteric inhibitor of substrate recognition by the SCF(Cdc4) ubiquitin ligase. Nat Biotechnol. 2010 Jul;28(7):733-7. Epub 2010 Jun 27. PMID:20581844 doi:10.1038/nbt.1646
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