| Structural highlights
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]
Publication Abstract from PubMed
The ubiquitin ligase SCF(Cdc4) (Skp1/Cul1/F-box protein) recognizes its substrate, the cyclin-dependent kinase inhibitor Sic1, in a multisite phosphorylation-dependent manner. Although short diphosphorylated peptides derived from Sic1 can bind to Cdc4 with high affinity, through systematic mutagenesis and quantitative biophysical analysis we show that individually weak, dispersed Sic1 phospho sites engage Cdc4 in a dynamic equilibrium. The affinities of individual phosphoepitopes serve to tune the overall phosphorylation site threshold needed for efficient recognition. Notably, phosphoepitope affinity for Cdc4 is dramatically weakened in the context of full-length Sic1, demonstrating the importance of regional environment on binding interactions. The multisite nature of the Sic1-Cdc4 interaction confers cooperative dependence on kinase activity for Sic1 recognition and ubiquitination under equilibrium reaction conditions. Composite dynamic interactions of low affinity sites may be a general mechanism to establish phosphorylation thresholds in biological responses.
Composite low affinity interactions dictate recognition of the cyclin-dependent kinase inhibitor Sic1 by the SCFCdc4 ubiquitin ligase.,Tang X, Orlicky S, Mittag T, Csizmok V, Pawson T, Forman-Kay JD, Sicheri F, Tyers M Proc Natl Acad Sci U S A. 2012 Feb 28;109(9):3287-92. Epub 2012 Feb 10. PMID:22328159[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
- ↑ Tang X, Orlicky S, Mittag T, Csizmok V, Pawson T, Forman-Kay JD, Sicheri F, Tyers M. Composite low affinity interactions dictate recognition of the cyclin-dependent kinase inhibitor Sic1 by the SCFCdc4 ubiquitin ligase. Proc Natl Acad Sci U S A. 2012 Feb 28;109(9):3287-92. Epub 2012 Feb 10. PMID:22328159 doi:10.1073/pnas.1116455109
|
