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AAA+ protease-adaptor structures reveal altered conformations and ring specialization

View ORCID ProfileSora Kim, View ORCID ProfileXue Fei, View ORCID ProfileRobert T. Sauer, View ORCID ProfileTania A. Baker
doi: https://doi.org/10.1101/2022.02.04.479121
Sora Kim
1Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139
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Xue Fei
1Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139
2Kymera Therapeutics Inc., Watertown, MA 02472
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Robert T. Sauer
1Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139
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Tania A. Baker
1Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139
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  • For correspondence: tabaker@mit.edu
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Summary

ClpAP, a two-ring AAA+ protease, degrades N-end-rule proteins bound by the ClpS adaptor. Here, we present high-resolution cryo-EM structures of ClpAPS complexes showing how ClpA pore loops interact with the ClpS N-terminal extension (NTE), which is normally intrinsically disordered. In two structural classes, the NTE is bound by a spiral of pore-1 and pore-2 loops in a manner similar to substrate-polypeptide binding by many AAA+ unfoldases. Kinetic studies reveal that pore-2 loops of the ClpA D1 ring catalyze protein remodeling required for substrate delivery by ClpS. In a third class, D2 pore-1 loops are rotated and tucked away from the channel, and do not bind the NTE, demonstrating asymmetry in engagement by the D1 and D2 rings. These studies demonstrate new structures and functions for key AAA+ elements. In addition to ClpAPS delivery, pore-loop tucking may be used broadly by AAA+ unfoldases, for example during enzyme pausing/unloading.

Competing Interest Statement

The authors have declared no competing interest.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Posted February 04, 2022.
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AAA+ protease-adaptor structures reveal altered conformations and ring specialization
Sora Kim, Xue Fei, Robert T. Sauer, Tania A. Baker
bioRxiv 2022.02.04.479121; doi: https://doi.org/10.1101/2022.02.04.479121
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AAA+ protease-adaptor structures reveal altered conformations and ring specialization
Sora Kim, Xue Fei, Robert T. Sauer, Tania A. Baker
bioRxiv 2022.02.04.479121; doi: https://doi.org/10.1101/2022.02.04.479121

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