Mechanical Protein Unfolding and Degradation

Author:

Olivares Adrian O.1,Baker Tania A.2,Sauer Robert T.3

Affiliation:

1. Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, USA

2. Howard Hughes Medical Institute and Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA

3. Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA;

Abstract

AAA+ proteolytic machines use energy from ATP hydrolysis to degrade damaged, misfolded, or unneeded proteins. Protein degradation occurs within a barrel-shaped self-compartmentalized peptidase. Before protein substrates can enter this peptidase, they must be unfolded and then translocated through the axial pore of an AAA+ ring hexamer. An unstructured region of the protein substrate is initially engaged in the axial pore, and conformational changes in the ring, powered by ATP hydrolysis, generate a mechanical force that pulls on and denatures the substrate. The same conformational changes in the hexameric ring then mediate mechanical translocation of the unfolded polypeptide into the peptidase chamber. For the bacterial ClpXP and ClpAP AAA+ proteases, the mechanical activities of protein unfolding and translocation have been directly visualized by single-molecule optical trapping. These studies in combination with structural and biochemical experiments illuminate many principles that underlie this universal mechanism of ATP-fueled protein unfolding and subsequent destruction.

Publisher

Annual Reviews

Subject

Physiology

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