Establishing Order Through Disorder by the Hsp90 Molecular Chaperone

Neethu Babu, Brian C. Freeman

Research output: Contribution to journalReview articlepeer-review

Abstract

The Heat Shock Protein 90 (Hsp90) molecular chaperone is a key driver of protein homeostasis (proteostasis) under physiologically normal and stress conditions. In eukaryotes, Hsp90 is essential and is one of the most abundant proteins in a cell where the chaperone shuttles between the cytoplasm and nucleus to fold, stabilize, and regulate client proteins and protein complexes. Numerous high-throughput screens have mapped the Hsp90 interactome, building a vast network comprising ∼25% of the proteome in budding yeast. How Hsp90 is able to associate with this diverse and large cadre of targets is critical to comprehending how the proteostatic process works. Here, we review recent progress on our understanding of the molecular underpinnings driving Hsp90-client interactions from both the perspective of the targets and Hsp90. In addition to considering the available Hsp90-client structures, we also assessed recently identified Hsp90-client peptide complexes to build a model that justifies how Hsp90 might recognize a wide spectrum of target proteins. In brief, Hsp90 either directly recognizes a site within an intrinsically disordered region (IDR) of a client protein to transiently regulate that client or it associates with an unstructured polypeptide section created by the concerted efforts of multiple chaperones and cochaperones to stably associate with a client. Overall, Hsp90 exploits a common recognition property (i.e., IDR) within diverse clients to support chaperone-action thereby enabling its central role in proteostasis.

Original languageEnglish (US)
Article number168460
JournalJournal of Molecular Biology
Volume436
Issue number14
DOIs
StatePublished - Jul 15 2024

Keywords

  • Heat Shock Protein 90
  • Hsp90
  • IDR
  • Intrinsically Disordered Regions
  • Molecular Chaperone

ASJC Scopus subject areas

  • Biophysics
  • Structural Biology
  • Molecular Biology

Fingerprint

Dive into the research topics of 'Establishing Order Through Disorder by the Hsp90 Molecular Chaperone'. Together they form a unique fingerprint.

Cite this