Tripartite degrons confer diversity and specificity on regulated protein degradation in the ubiquitin-proteasome system

• Published in: Nature communications 2016-01, Vol.7 (1), p.10239-13, Article 10239
• Main Authors: Guharoy, Mainak, Bhowmick, Pallab, Sallam, Mohamed, Tompa, Peter
• Format: Article
• Language: English
• Subjects: 631/1647/48; 631/337/474/2085; 631/45/474; 631/45/612/645; 82; Animals; Gene Expression Regulation; Humanities and Social Sciences; Humans; Mammals; Models, Molecular; multidisciplinary; Proteasome Endopeptidase Complex - metabolism; Protein Conformation; Proteins - genetics; Proteins - metabolism; Proteolysis; Science; Science (multidisciplinary); Ubiquitins - metabolism
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/ncomms10239

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. Degrons are determinants within proteins that direct programmed degradation by the ubiquitinproteasome system. Here, the authors propose a three-part degron architecture which contains an E3-ligase recognition motif, a ubiquitination site(s), and a disordered site to initiate degradation.