Ubiquitin binding by a CUE domain regulates ubiquitin chain formation by ERAD E3 ligases

Katrin Bagola; Maximilian von Delbrück; Gunnar Dittmar; Martin Scheffner; Inbal Ziv; Michael H Glickman; Aaron Ciechanover; Thomas Sommer

doi:10.1016/j.molcel.2013.04.005

Ubiquitin binding by a CUE domain regulates ubiquitin chain formation by ERAD E3 ligases

Mol Cell. 2013 May 23;50(4):528-39. doi: 10.1016/j.molcel.2013.04.005. Epub 2013 May 9.

Authors

Katrin Bagola¹, Maximilian von Delbrück, Gunnar Dittmar, Martin Scheffner, Inbal Ziv, Michael H Glickman, Aaron Ciechanover, Thomas Sommer

Affiliation

¹ Max-Delbrück-Center for Molecular Medicine, Robert-Rössle-Strasse 10, D-13122 Berlin, Germany.

PMID: 23665229
DOI: 10.1016/j.molcel.2013.04.005

Abstract

Ubiquitin-binding domains (UBDs) differentially recognize ubiquitin (ub) modifications. Some of them specifically bind mono-ub, as has been shown for the CUE domain. Interestingly, so far no significant ubiquitin binding has been observed for the CUE domain of yeast Cue1p. Cue1p is receptor and activator of the ubiquitin-conjugating enzyme Ubc7p. It integrates Ubc7p into endoplasmic reticulum (ER) membrane-bound ubiquitin ligase complexes, and thus, it is crucial for ER-associated protein degradation (ERAD). Here we show that the CUE domain of Cue1p binds ubiquitin chains, which is pivotal for the efficient formation of K48-linked polyubiquitin chains in vitro. Mutations that abolish ubiquitin binding by Cue1p affect the turnover of ERAD substrates in vivo. Our data strongly imply that the CUE domain facilitates substrate ubiquitylation by stabilizing growing ubiquitin chains at the ERAD ubiquitin ligases. Hence, we demonstrate an unexpected function of a UBD in the regulation of ubiquitin chain synthesis.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Amino Acid Sequence
Binding Sites / genetics
Carrier Proteins / chemistry
Carrier Proteins / genetics
Carrier Proteins / metabolism*
Electrophoresis, Polyacrylamide Gel
Endoplasmic Reticulum / metabolism*
Lysine / genetics
Lysine / metabolism
Membrane Proteins / chemistry
Membrane Proteins / genetics
Membrane Proteins / metabolism*
Molecular Sequence Data
Mutation
Polyubiquitin / metabolism
Protein Structure, Tertiary
Saccharomyces cerevisiae Proteins / chemistry
Saccharomyces cerevisiae Proteins / genetics
Saccharomyces cerevisiae Proteins / metabolism*
Sequence Homology, Amino Acid
Ubiquitin / genetics
Ubiquitin / metabolism*
Ubiquitin-Conjugating Enzymes / genetics
Ubiquitin-Conjugating Enzymes / metabolism
Ubiquitin-Protein Ligases / genetics
Ubiquitin-Protein Ligases / metabolism*
Ubiquitination

Substances

CUE1 protein, S cerevisiae
Carrier Proteins
Membrane Proteins
Saccharomyces cerevisiae Proteins
Ubiquitin
Polyubiquitin
UBC7 protein, S cerevisiae
Ubiquitin-Conjugating Enzymes
HRD1 protein, S cerevisiae
Ubiquitin-Protein Ligases
Lysine