Specific and Fuzzy Interactions Cooperate in Modulating Protein Half-Life

Rashmi Sharma, Máté Demény, Viktor Ambrus, Sándor Balázs Király, Tibor Kurtán, Pietro Gatti-Lafranconi, Monika Fuxreiter

Research output: Contribution to journalArticle

Abstract

Protein degradation is critical for maintaining cellular homeostasis. The 20S proteasome is selective for unfolded, extended polypeptide chains without ubiquitin tags. Sequestration of such segments by protein partners, however, may provide a regulatory mechanism. Here we used the AP-1 complex to study how c-Fos turnover is controlled by interactions with c-Jun. We show that heterodimerization with c-Jun increases c-Fos half-life. Mutations affecting specific contact sites (L165V, L172V) or charge separation (E175D, E189D, K190R) with c-Jun both modulate c-Fos turnover, proportionally to their impact on binding affinity. The fuzzy tail beyond the structured b-HLH/ZIP domain (~ 165 residues) also contributes to the stabilization of the AP-1 complex, removal of which decreases c-Fos half-life. Thus, protein turnover by 20S proteasome is fine-tuned by both specific and fuzzy interactions, consistently with the previously proposed “nanny” model.

Original languageEnglish
Pages (from-to)1700-1707
Number of pages8
JournalJournal of molecular biology
Volume431
Issue number8
DOIs
Publication statusPublished - Apr 5 2019

Keywords

  • 20S proteasome
  • AP-1 complex
  • fuzzy complex
  • nanny model
  • protein degradation

ASJC Scopus subject areas

  • Structural Biology
  • Molecular Biology

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