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

Author

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  • Lorea Velasco-Carneros

    (University of the Basque Country
    University of the Basque Country (UPV/EHU))

  • Jorge Cuéllar

    (National Centre for Biotechnology (CNB-CSIC))

  • Leire Dublang

    (University of the Basque Country
    University of the Basque Country (UPV/EHU))

  • César Santiago

    (National Centre for Biotechnology (CNB-CSIC))

  • Jean-Didier Maréchal

    (Universitat Autònoma de Barcelona, (UAB))

  • Jaime Martín-Benito

    (National Centre for Biotechnology (CNB-CSIC))

  • Moisés Maestro

    (National Centre for Biotechnology (CNB-CSIC))

  • José Ángel Fernández-Higuero

    (University of the Basque Country
    University of the Basque Country (UPV/EHU))

  • Natalia Orozco

    (University of the Basque Country)

  • Fernando Moro

    (University of the Basque Country
    University of the Basque Country (UPV/EHU))

  • José María Valpuesta

    (National Centre for Biotechnology (CNB-CSIC))

  • Arturo Muga

    (University of the Basque Country
    University of the Basque Country (UPV/EHU))

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.

Suggested Citation

  • 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 & , 2023. "The self-association equilibrium of DNAJA2 regulates its interaction with unfolded substrate proteins and with Hsc70," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-41150-8
    DOI: 10.1038/s41467-023-41150-8
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    1. Nadinath B. Nillegoda & Janine Kirstein & Anna Szlachcic & Mykhaylo Berynskyy & Antonia Stank & Florian Stengel & Kristin Arnsburg & Xuechao Gao & Annika Scior & Ruedi Aebersold & D. Lys Guilbride & R, 2015. "Crucial HSP70 co-chaperone complex unlocks metazoan protein disaggregation," Nature, Nature, vol. 524(7564), pages 247-251, August.
    2. Ofrah Faust & Meital Abayev-Avraham & Anne S. Wentink & Michael Maurer & Nadinath B. Nillegoda & Nir London & Bernd Bukau & Rina Rosenzweig, 2020. "HSP40 proteins use class-specific regulation to drive HSP70 functional diversity," Nature, Nature, vol. 587(7834), pages 489-494, November.
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