Design Principles Involving Protein Disorder Facilitate Specific Substrate Selection and Degradation by the Ubiquitin-Proteasome System.

TitleDesign Principles Involving Protein Disorder Facilitate Specific Substrate Selection and Degradation by the Ubiquitin-Proteasome System.
Publication TypeJournal Article
Year of Publication2016
AuthorsGuharoy, M., Bhowmick P., and Tompa P.
JournalJ Biol Chem
Volume291
Issue13
Pagination6723-31
Date Published2016 Mar 25
ISSN1083-351X
KeywordsAmino Acid Motifs, Humans, Intrinsically Disordered Proteins, Molecular Sequence Annotation, Molecular Sequence Data, Proteasome Endopeptidase Complex, Protein Binding, Protein Folding, Protein Interaction Domains and Motifs, Protein Processing, Post-Translational, Protein Structure, Secondary, Proteolysis, Substrate Specificity, Ubiquitin, Ubiquitin-Protein Ligases, Ubiquitination
Abstract

The ubiquitin-proteasome system (UPS) regulates diverse cellular pathways by the timely removal (or processing) of proteins. Here we review the role of structural disorder and conformational flexibility in the different aspects of degradation. First, we discuss post-translational modifications within disordered regions that regulate E3 ligase localization, conformation, and enzymatic activity, and also the role of flexible linkers in mediating ubiquitin transfer and reaction processivity. Next we review well studied substrates and discuss that substrate elements (degrons) recognized by E3 ligases are highly disordered: short linear motifs recognized by many E3s constitute an important class of degrons, and these are almost always present in disordered regions. Substrate lysines targeted for ubiquitination are also often located in neighboring regions of the E3 docking motifs and are therefore part of the disordered segment. Finally, biochemical experiments and predictions show that initiation of degradation at the 26S proteasome requires a partially unfolded region to facilitate substrate entry into the proteasomal core.

DOI10.1074/jbc.R115.692665
Alternate JournalJ. Biol. Chem.
PubMed ID26851277
PubMed Central IDPMC4807260
Research group: