title: Design Principles Involving Protein Disorder Facilitate Specific Substrate Selection and Degradation by the Ubiquitin-Proteasome System.
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.
authors: From the VIB Structural Biology Research Center (SBRC), Vlaams Instituut voor Biotechnologie, 1050 Brussel, Belgium, the Structural Biology Brussels (SBB), Vrije Universiteit Brussel, 1050 Brussels, Belgium, and mainak.guharoy@vib-vub.be.
authors: Mainak
authors: M
authors: Guharoy
authors: From the VIB Structural Biology Research Center (SBRC), Vlaams Instituut voor Biotechnologie, 1050 Brussel, Belgium, the Structural Biology Brussels (SBB), Vrije Universiteit Brussel, 1050 Brussels, Belgium, and.
authors: Pallab
authors: P
authors: Bhowmick
authors: From the VIB Structural Biology Research Center (SBRC), Vlaams Instituut voor Biotechnologie, 1050 Brussel, Belgium, the Structural Biology Brussels (SBB), Vrije Universiteit Brussel, 1050 Brussels, Belgium, and the Institute of Enzymology, Research Centre for Natural Sciences of the Hungarian Academy of Sciences, 1117 Budapest, Hungary ptompa@vub.ac.be.
authors: Peter
authors: P
authors: Tompa
mesh_terms: D020816:Amino Acid Motifs; D006801:Humans; D064267:Intrinsically Disordered Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D058977:Molecular Sequence Annotation; D008969:Molecular Sequence Data; D046988:Proteasome Endopeptidase Complex / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D017510:Protein Folding; D054730:Protein Interaction Domains and Motifs; D011499:Protein Processing, Post-Translational; D017433:Protein Structure, Secondary; D059748:Proteolysis; D013379:Substrate Specificity; D025801:Ubiquitin / Q000235:genetics / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D054875:Ubiquitination
chemical_list: D064267:Intrinsically Disordered Proteins; D025801:Ubiquitin; D044767:Ubiquitin-Protein Ligases; D046988:Proteasome Endopeptidase Complex; C061553:ATP dependent 26S protease
keywords: E3 ligase; E3 ubiquitin ligase; intrinsically disordered protein; proteasome; protein degradation; protein phosphorylation; protein structural disorder; regulated degradation; ubiquitylation (ubiquitination)