Structural Basis for a Reciprocal Regulation between SCF and CSN
Skp1-Cul1-Fbox (SCF) E3 ligases are activated by ligation to the ubiquitin-like protein Nedd8, which is reversed by the deneddylating Cop9 signalosome (CSN). However, CSN also promotes SCF substrate turnover through unknown mechanisms. Through biochemical and electron microscopy analyses, we determ...
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doaj-95d27973a68a4db69a2cc1b77c5f37352020-11-24T21:47:27ZengElsevierCell Reports2211-12472012-09-012361662710.1016/j.celrep.2012.08.019Structural Basis for a Reciprocal Regulation between SCF and CSNRadoslav I. Enchev0Daniel C. Scott1Paula C.A. da Fonseca2Anne Schreiber3Julie K. Monda4Brenda A. Schulman5Matthias Peter6Edward P. Morris7ETH-Zurich, Institute of Biochemistry, Department of Biology, Schafmattstr. 18, CH-8093 Zurich, SwitzerlandDepartment of Structural Biology, St. Jude Children’s Research Hospital, Memphis, TN 38105, USADivision of Structural Biology, The Institute of Cancer Research, Chester Beatty Laboratories, 237 Fulham Road, London SW3 6JB, UKDivision of Structural Biology, The Institute of Cancer Research, Chester Beatty Laboratories, 237 Fulham Road, London SW3 6JB, UKDepartment of Structural Biology, St. Jude Children’s Research Hospital, Memphis, TN 38105, USADepartment of Structural Biology, St. Jude Children’s Research Hospital, Memphis, TN 38105, USAETH-Zurich, Institute of Biochemistry, Department of Biology, Schafmattstr. 18, CH-8093 Zurich, SwitzerlandDivision of Structural Biology, The Institute of Cancer Research, Chester Beatty Laboratories, 237 Fulham Road, London SW3 6JB, UK Skp1-Cul1-Fbox (SCF) E3 ligases are activated by ligation to the ubiquitin-like protein Nedd8, which is reversed by the deneddylating Cop9 signalosome (CSN). However, CSN also promotes SCF substrate turnover through unknown mechanisms. Through biochemical and electron microscopy analyses, we determined molecular models of CSN complexes with SCFSkp2/Cks1 and SCFFbw7 and found that CSN occludes both SCF functional sites—the catalytic Rbx1-Cul1 C-terminal domain and the substrate receptor. Indeed, CSN binding prevents SCF interactions with E2 enzymes and a ubiquitination substrate, and it inhibits SCF-catalyzed ubiquitin chain formation independent of deneddylation. Importantly, CSN prevents neddylation of the bound cullin, unless binding of a ubiquitination substrate triggers SCF dissociation and neddylation. Taken together, the results provide a model for how reciprocal regulation sensitizes CSN to the SCF assembly state and inhibits a catalytically competent SCF until a ubiquitination substrate drives its own degradation by displacing CSN, thereby promoting cullin neddylation and substrate ubiquitination. http://www.sciencedirect.com/science/article/pii/S2211124712002598 |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Radoslav I. Enchev Daniel C. Scott Paula C.A. da Fonseca Anne Schreiber Julie K. Monda Brenda A. Schulman Matthias Peter Edward P. Morris |
spellingShingle |
Radoslav I. Enchev Daniel C. Scott Paula C.A. da Fonseca Anne Schreiber Julie K. Monda Brenda A. Schulman Matthias Peter Edward P. Morris Structural Basis for a Reciprocal Regulation between SCF and CSN Cell Reports |
author_facet |
Radoslav I. Enchev Daniel C. Scott Paula C.A. da Fonseca Anne Schreiber Julie K. Monda Brenda A. Schulman Matthias Peter Edward P. Morris |
author_sort |
Radoslav I. Enchev |
title |
Structural Basis for a Reciprocal Regulation between SCF and CSN |
title_short |
Structural Basis for a Reciprocal Regulation between SCF and CSN |
title_full |
Structural Basis for a Reciprocal Regulation between SCF and CSN |
title_fullStr |
Structural Basis for a Reciprocal Regulation between SCF and CSN |
title_full_unstemmed |
Structural Basis for a Reciprocal Regulation between SCF and CSN |
title_sort |
structural basis for a reciprocal regulation between scf and csn |
publisher |
Elsevier |
series |
Cell Reports |
issn |
2211-1247 |
publishDate |
2012-09-01 |
description |
Skp1-Cul1-Fbox (SCF) E3 ligases are activated by ligation to the ubiquitin-like protein Nedd8, which is reversed by the deneddylating Cop9 signalosome (CSN). However, CSN also promotes SCF substrate turnover through unknown mechanisms. Through biochemical and electron microscopy analyses, we determined molecular models of CSN complexes with SCFSkp2/Cks1 and SCFFbw7 and found that CSN occludes both SCF functional sites—the catalytic Rbx1-Cul1 C-terminal domain and the substrate receptor. Indeed, CSN binding prevents SCF interactions with E2 enzymes and a ubiquitination substrate, and it inhibits SCF-catalyzed ubiquitin chain formation independent of deneddylation. Importantly, CSN prevents neddylation of the bound cullin, unless binding of a ubiquitination substrate triggers SCF dissociation and neddylation. Taken together, the results provide a model for how reciprocal regulation sensitizes CSN to the SCF assembly state and inhibits a catalytically competent SCF until a ubiquitination substrate drives its own degradation by displacing CSN, thereby promoting cullin neddylation and substrate ubiquitination.
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url |
http://www.sciencedirect.com/science/article/pii/S2211124712002598 |
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