title: Tripartite degrons confer diversity and specificity on regulated protein degradation in the ubiquitin-proteasome system.
abstract: Specific signals (degrons) regulate protein turnover mediated by the ubiquitin-proteasome system. Here we systematically analyse known degrons and propose a tripartite model comprising the following: (1) a primary degron (peptide motif) that specifies substrate recognition by cognate E3 ubiquitin ligases, (2) secondary site(s) comprising a single or multiple neighbouring ubiquitinated lysine(s) and (3) a structurally disordered segment that initiates substrate unfolding at the 26S proteasome. Primary degron sequences are conserved among orthologues and occur in structurally disordered regions that undergo E3-induced folding-on-binding. Posttranslational modifications can switch primary degrons into E3-binding-competent states, thereby integrating degradation with signalling pathways. Degradation-linked lysines tend to be located within disordered segments that also initiate substrate degradation by effective proteasomal engagement. Many characterized mutations and alternative isoforms with abrogated degron components are implicated in disease. These effects result from increased protein stability and interactome rewiring. The distributed nature of degrons ensures regulation, specificity and combinatorial control of degradation.
authors.affiliation: VIB Structural Biology Research Center (SBRC), Vrije Universiteit Brussel (VUB), Building E, Pleinlaan 2, 1050 Brussels, Belgium.
authors.forename: Mainak
authors.initials: M
authors.lastname: Guharoy
authors.affiliation: VIB Structural Biology Research Center (SBRC), Vrije Universiteit Brussel (VUB), Building E, Pleinlaan 2, 1050 Brussels, Belgium.
authors.forename: Pallab
authors.initials: P
authors.lastname: Bhowmick
authors.affiliation: VIB Structural Biology Research Center (SBRC), Vrije Universiteit Brussel (VUB), Building E, Pleinlaan 2, 1050 Brussels, Belgium.
authors.forename: Mohamed
authors.initials: M
authors.lastname: Sallam
authors.affiliation: VIB Structural Biology Research Center (SBRC), Vrije Universiteit Brussel (VUB), Building E, Pleinlaan 2, 1050 Brussels, Belgium.|Institute of Enzymology, Research Center for Natural Sciences, Hungarian Academy of Sciences, 1117 Budapest, Hungary.
authors.forename: Peter
authors.initials: P
authors.lastname: Tompa
mesh_terms: D000818:Animals; D005786:Gene Expression Regulation; D006801:Humans; D008322:Mammals; D008958:Models, Molecular; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D011487:Protein Conformation; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D059748:Proteolysis; D014452:Ubiquitins / Q000378:metabolism*
chemical_list: D011506:Proteins; D014452:Ubiquitins; D046988:Proteasome Endopeptidase Complex