A proteolytic AAA+ machine poised to unfold protein substrates

Alireza Ghanbarpour, Robert T. Sauer () and Joseph H. Davis ()
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Alireza Ghanbarpour: Washington University in St. Louis
Robert T. Sauer: Massachusetts Institute of Technology
Joseph H. Davis: Massachusetts Institute of Technology

Nature Communications, 2024, vol. 15, issue 1, 1-10

Abstract: Abstract AAA+ proteolytic machines unfold proteins before degrading them. Here, we present cryoEM structures of ClpXP-substrate complexes that reveal a postulated but heretofore unseen intermediate in substrate unfolding/degradation. A ClpX hexamer draws natively folded substrates tightly against its axial channel via interactions with a fused C-terminal degron tail and ClpX-RKH loops that flexibly conform to the globular substrate. The specific ClpX-substrate contacts observed vary depending on the substrate degron and affinity tags, helping to explain ClpXP’s ability to unfold/degrade a wide array of different cellular substrates. Some ClpX contacts with native substrates are enabled by upward movement of the seam subunit in the AAA+ spiral, a motion coupled to a rearrangement of contacts between the ClpX unfoldase and ClpP peptidase. Our structures additionally highlight ClpX’s ability to translocate a diverse array of substrate topologies, including the co-translocation of two polypeptide chains.

Date: 2024
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DOI: 10.1038/s41467-024-53681-9

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