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Structure of a AAA+ unfoldase in the process of unfolding substrate.

Structure of a AAA+ unfoldase in the process of unfolding substrate.
Author Information (click to view)

Ripstein ZA, Huang R, Augustyniak R, Kay LE, Rubinstein JL,


Ripstein ZA, Huang R, Augustyniak R, Kay LE, Rubinstein JL, (click to view)

Ripstein ZA, Huang R, Augustyniak R, Kay LE, Rubinstein JL,

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eLife 2017 04 086() doi 10.7554/eLife.25754
Abstract

AAA+ unfoldases are thought to unfold substrate through the central pore of their hexameric structures, but how this process occurs is not known. VAT, the Thermoplasma acidophilum homologue of eukaryotic CDC48/p97, works in conjunction with the proteasome to degrade misfolded or damaged proteins. We show that in the presence of ATP, VAT with its regulatory N-terminal domains removed unfolds other VAT complexes as substrate. We captured images of this transient process by electron cryomicroscopy (cryo-EM) to reveal the structure of the substrate-bound intermediate. Substrate binding breaks the six-fold symmetry of the complex, allowing five of the six VAT subunits to constrict into a tight helix that grips an ~80 Å stretch of unfolded protein. The structure suggests a processive hand-over-hand unfolding mechanism, where each VAT subunit releases the substrate in turn before re-engaging further along the target protein, thereby unfolding it.

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