Head-to-tail interactions of the coiled-coil domains regulate ClpB cooperation with Hsp70 in protein disaggregation

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Abstract

The hexameric AAA+ chaperone ClpB reactivates aggregated proteins in cooperation with the Hsp70 system. Essential for disaggregation, the ClpB middle domain (MD) is a coiled-coil propeller that binds Hsp70. Although the ClpB subunit structure is known, positioning of the MD in the hexamer and its mechanism of action are unclear. We obtained electron microscopy (EM) structures of the BAP variant of ClpB that binds the protease ClpP, clearly revealing MD density on the surface of the ClpB ring. Mutant analysis and asymmetric reconstructions show that MDs adopt diverse positions in a single ClpB hexamer. Adjacent, horizontally oriented MDs form head-to-tail contacts and repress ClpB activity by preventing Hsp70 interaction. Tilting of the MD breaks this contact, allowing Hsp70 binding, and releasing the contact in adjacent subunits. Our data suggest a wavelike activation of ClpB subunits around the ring.

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Marta Carroni

Birkbeck College, University of London, London, United Kingdom

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The authors declare that no competing interests exist.
Eva Kummer

Zentrum für Molekulare Biologie der Universität Heidelberg, Heidelberg, Germany

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Yuki Oguchi

Zentrum für Molekulare Biologie der Universität Heidelberg, Heidelberg, Germany

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Petra Wendler

Ludwig-Maximilians-University Munich, Munich, Germany

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Daniel K Clare

Birkbeck College, University of London, London, United Kingdom

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Irmgard Sinning

Biochemie-Zentrum der Universität Heidelberg (BZH), Heidelberg, Germany

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Jürgen Kopp

Biochemie-Zentrum der Universität Heidelberg (BZH), Heidelberg, Germany

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Axel Mogk

Zentrum für Molekulare Biologie der Universität Heidelberg, Heidelberg, Germany

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Bernd Bukau

Zentrum für Molekulare Biologie der Universität Heidelberg, Heidelberg, Germany

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Helen Saibil

Birkbeck College, University of London, London, United Kingdom

For correspondence
h.saibil@mail.cryst.bbk.ac.uk

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The authors declare that no competing interests exist.

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