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Title: Structural basis for phosphodependent substrate selection and orientation by the SCFCdc4 ubiquitin ligase

Abstract

Cell cycle progression depends on precise elimination of cyclins and cyclin-dependent kinase (CDK) inhibitors by the ubiquitin system. Elimination of the CDK inhibitor Sic1 by the SCF{sup Cdc4} ubiquitin ligase at the onset of S phase requires phosphorylation of Sic1 on at least six of its nine Cdc4-phosphodegron (CPD) sites. A 2.7 {angstrom} X-ray crystal structure of a Skp1-Cdc4 complex bound to a high-affinity CPD phosphopeptide from human cyclin E reveals a core CPD motif, Leu-Leu-pThr-Pro, bound to an eight-bladed WD40 propeller domain in Cdc4. The low affinity of each CPD motif in Sic1 reflects structural discordance with one or more elements of the Cdc4 binding site. Reengineering of Cdc4 to reduce selection against Sic1 sequences allows ubiquitination of lower phosphorylated forms of Sic1. These features account for the observed phosphorylation threshold in Sic1 recognition and suggest an equilibrium binding mode between a single receptor site in Cdc4 and multiple low-affinity CPD sites in Sic1.

Authors:
; ; ; ;
Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Org.:
USDOE
OSTI Identifier:
1008763
Resource Type:
Journal Article
Journal Name:
Cell
Additional Journal Information:
Journal Volume: 112; Journal Issue: (2) ; 2003; Journal ID: ISSN 0092-8674
Country of Publication:
United States
Language:
ENGLISH
Subject:
36 MATERIALS SCIENCE; AFFINITY; CELL CYCLE; CRYSTAL STRUCTURE; LIGASES; ORIENTATION; PHOSPHORYLATION; PHOSPHOTRANSFERASES; SUBSTRATES

Citation Formats

Orlicky, Steve, Tang, Xiaojing, Willems, Andrew, Tyers, Mike, and Sicheri, Frank. Structural basis for phosphodependent substrate selection and orientation by the SCFCdc4 ubiquitin ligase. United States: N. p., 2010. Web.
Orlicky, Steve, Tang, Xiaojing, Willems, Andrew, Tyers, Mike, & Sicheri, Frank. Structural basis for phosphodependent substrate selection and orientation by the SCFCdc4 ubiquitin ligase. United States.
Orlicky, Steve, Tang, Xiaojing, Willems, Andrew, Tyers, Mike, and Sicheri, Frank. 2010. "Structural basis for phosphodependent substrate selection and orientation by the SCFCdc4 ubiquitin ligase". United States.
@article{osti_1008763,
title = {Structural basis for phosphodependent substrate selection and orientation by the SCFCdc4 ubiquitin ligase},
author = {Orlicky, Steve and Tang, Xiaojing and Willems, Andrew and Tyers, Mike and Sicheri, Frank},
abstractNote = {Cell cycle progression depends on precise elimination of cyclins and cyclin-dependent kinase (CDK) inhibitors by the ubiquitin system. Elimination of the CDK inhibitor Sic1 by the SCF{sup Cdc4} ubiquitin ligase at the onset of S phase requires phosphorylation of Sic1 on at least six of its nine Cdc4-phosphodegron (CPD) sites. A 2.7 {angstrom} X-ray crystal structure of a Skp1-Cdc4 complex bound to a high-affinity CPD phosphopeptide from human cyclin E reveals a core CPD motif, Leu-Leu-pThr-Pro, bound to an eight-bladed WD40 propeller domain in Cdc4. The low affinity of each CPD motif in Sic1 reflects structural discordance with one or more elements of the Cdc4 binding site. Reengineering of Cdc4 to reduce selection against Sic1 sequences allows ubiquitination of lower phosphorylated forms of Sic1. These features account for the observed phosphorylation threshold in Sic1 recognition and suggest an equilibrium binding mode between a single receptor site in Cdc4 and multiple low-affinity CPD sites in Sic1.},
doi = {},
url = {https://www.osti.gov/biblio/1008763}, journal = {Cell},
issn = {0092-8674},
number = (2) ; 2003,
volume = 112,
place = {United States},
year = {Wed Dec 01 00:00:00 EST 2010},
month = {Wed Dec 01 00:00:00 EST 2010}
}