Cullin neddylation and substrate-adaptors counteract SCF inhibition by the CAND1-like protein Lag2 in Saccharomyces cerevisiae.

The EMBO Journal
Edyta SiergiejukMatthias Peter

Abstract

Cullin-based E3 ubiquitin ligases are activated through covalent modification of the cullin subunit by the ubiquitin-like protein Nedd8. Cullin neddylation dissociates the ligase assembly inhibitor Cand1, and promotes E2 recruitment and ubiquitin transfer by inducing a conformational change. Here, we have identified and characterized Lag2 as a likely Saccharomyces cerevisiae orthologue of mammalian Cand1. Similar to Cand1, Lag2 directly interacts with non-neddylated yeast cullin Cdc53 and prevents its neddylation in vivo and in vitro. Binding occurs through a conserved C-terminal beta-hairpin structure that inserts into the Skp1-binding pocket on the cullin, and an N-terminal motif that covers the neddylation lysine. Interestingly, Lag2 is itself neddylated in vivo on a lysine adjacent to this N-terminal-binding site. Overexpression of Lag2 inhibits Cdc53 activity in strains defective for Skp1 or neddylation functions, implying that these activities are important to counteract Lag2 in vivo. Our results favour a model in which binding of substrate-specific adaptors triggers release of Cand1/Lag2, whereas subsequent neddylation of the cullin facilitates the removal and prevents re-association of Lag2/Cand1.

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Citations

Mar 29, 2013·Nature Communications·Shuangding WuDieter A Wolf
Apr 30, 2014·Annual Review of Biophysics·Frederick C Streich, Christopher D Lima
Mar 29, 2013·Nature Communications·Aleksandra ZemlaThimo Kurz
Sep 13, 2015·Critical Reviews in Biochemistry and Molecular Biology·Kunio NakatsukasaTakumi Kamura
Oct 12, 2010·Current Opinion in Microbiology·Gerhard H BrausOzgür Bayram
Aug 6, 2011·Molecular Cell·Gwenaël RabutMatthias Peter
Sep 14, 2010·Molecular Cell·Daniel C ScottBrenda A Schulman
Sep 11, 2012·Cell Reports·Radoslav I EnchevEdward P Morris
Apr 9, 2014·Frontiers in Plant Science·Julia Mergner, Claus Schwechheimer
Dec 15, 2015·PLoS Genetics·Radhika MathurPeter Kaiser
Nov 18, 2017·PLoS Computational Biology·Ronny StraubeDieter A Wolf
Dec 19, 2017·Trends in Biochemical Sciences·Wolfgang DubielMichael Naumann
Sep 23, 2021·G3 : Genes - Genomes - Genetics·Lin ZhouFloris Foijer

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