TY - JOUR
T1 - The self-association equilibrium of DNAJA2 regulates its interaction with unfolded substrate proteins and with Hsc70
AU - Velasco-Carneros, Lorea
AU - Cuéllar, Jorge
AU - Dublang, Leire
AU - Santiago, César
AU - Maréchal, Jean Didier
AU - Martín-Benito, Jaime
AU - Maestro, Moisés
AU - Fernández-Higuero, José Ángel
AU - Orozco, Natalia
AU - Moro, Fernando
AU - Valpuesta, José María
AU - Muga, Arturo
N1 - Publisher Copyright:
© 2023, Springer Nature Limited.
PY - 2023/9/5
Y1 - 2023/9/5
N2 - 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.
AB - 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.
KW - Cryoelectron Microscopy
KW - HSP40 Heat-Shock Proteins
KW - HSP70 Heat-Shock Proteins
KW - Humans
KW - Mutation
KW - Polymers
UR - http://www.scopus.com/inward/record.url?scp=85169759304&partnerID=8YFLogxK
UR - https://www.mendeley.com/catalogue/5163033f-4462-361a-8617-821f18f2315b/
U2 - 10.1038/s41467-023-41150-8
DO - 10.1038/s41467-023-41150-8
M3 - Article
C2 - 37670029
AN - SCOPUS:85169759304
SN - 2041-1723
VL - 14
JO - Nature communications
JF - Nature communications
IS - 1
M1 - 5436
ER -