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

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 di...

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Detalhes bibliográficos
Autores: Velasco-Carneros, Lorea|||0000-0002-1296-9498, Cuéllar, Jorge|||0000-0002-7789-807X, Dublang, Leire, Santiago, César|||0000-0002-5149-1722, Maréchal, Jean-Didier|||0000-0002-8344-9043, Martín-Benito, Jaime|||0000-0002-8541-4709, Maestro, Moisés|||0000-0002-7955-9135, Fernández-Higuero, José Ángel, Orozco, Natalia, Moro, Fernando, Valpuesta, Jose María|||0000-0001-7468-8053, Muga, Arturo|||0000-0003-0345-6882
Formato: artículo
Fecha de publicación:2023
País:España
Recursos:Universitat Autònoma de Barcelona
Repositorio:Dipòsit Digital de Documents de la UAB
Idioma:inglés
OAI Identifier:oai:ddd.uab.cat:309074
Acesso em linha:https://ddd.uab.cat/record/309074
https://dx.doi.org/urn:doi:10.1038/s41467-023-41150-8
Access Level:acceso abierto
Palavra-chave:Cryoelectron microscopy
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Descrição
Resumo: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. J-domain proteins (JDPs) regulate Hsp70 function and specificity. Here, authors combine functional assays and cryoEM to describe the structure of a dynamic tubular assembly of DNAJA2, a class A JDP, and its stabilizing interdomain interactions.

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