The self-association equilibrium of DNAJA2 regulates its interaction with unfolded substrate proteins and with Hsc70

Lorea Velasco-Carneros, Jorge Cuéllar, Leire Dublang, César Santiago, Jean Didier Maréchal, Jaime Martín-Benito, Moisés Maestro, José Ángel Fernández-Higuero, Natalia Orozco, Fernando Moro, José María Valpuesta*, Arturo Muga*

*Corresponding author for this work

Research output: Contribution to journalArticleResearchpeer-review

6 Citations (Scopus)

Abstract

J-domain proteins tune the specificity of Hsp70s, engaging them in precise functions. Despite their essential role, the structure and function of many J-domain proteins remain largely unknown. We explore human DNAJA2, finding that it reversibly forms highly-ordered, tubular structures that can be dissociated by Hsc70, the constitutively expressed Hsp70 isoform. Cryoelectron microscopy and mutational studies reveal that different domains are involved in self-association. Oligomer dissociation into dimers potentiates its interaction with unfolded client proteins. The J-domains are accessible to Hsc70 within the tubular structure. They allow binding of closely spaced Hsc70 molecules that could be transferred to the unfolded substrate for its cooperative remodelling, explaining the efficient recovery of DNAJA2-bound clients. The disordered C-terminal domain, comprising the last 52 residues, regulates its holding activity and productive interaction with Hsc70. These in vitro findings suggest that the association equilibrium of DNAJA2 could regulate its interaction with client proteins and Hsc70.

Original languageEnglish
Article number5436
Number of pages16
JournalNature communications
Volume14
Issue number1
DOIs
Publication statusPublished - 5 Sept 2023

Keywords

  • Cryoelectron Microscopy
  • HSP40 Heat-Shock Proteins
  • HSP70 Heat-Shock Proteins
  • Humans
  • Mutation
  • Polymers

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