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Published May 10, 2013 | Published
Journal Article Open

Mechanism of an ATP-independent Protein Disaggregase. II. Distinct Molecular Interactions Drive Multiple Steps During Aggregate Disassembly


The ability of molecular chaperones to overcome the misfolding and aggregation of proteins is essential for the maintenance of proper protein homeostasis in all cells. Thus far, the best studied disaggregase systems are the Clp/Hsp100 family of "ATPases associated with various cellular activities" (AAA^+) ATPases, which use mechanical forces powered by ATP hydrolysis to remodel protein aggregates. An alternative system to disassemble large protein aggregates is provided by the 38-kDa subunit of the chloroplast signal recognition particle (cpSRP43), which uses binding energy with its substrate proteins to drive disaggregation. The mechanism of this novel chaperone remains unclear. Here, molecular genetics and structure-activity analyses show that the action of cpSRP43 can be dissected into two steps with distinct molecular requirements: (i) initial recognition, during which cpSRP43 binds specifically to a recognition motif displayed on the surface of the aggregate; and (ii) aggregate remodeling, during which highly adaptable binding interactions of cpSRP43 with hydrophobic transmembrane domains of the substrate protein compete with the packing interactions within the aggregate. This establishes a useful framework to understand the molecular mechanism by which binding interactions from a molecular chaperone can be used to overcome protein aggregates in the absence of external energy input from ATP.

Additional Information

© 2013 by The American Society for Biochemistry and Molecular Biology, Inc. Received February 18, 2013; Revision received March 12, 2013. Supported by the Department of Defense, National Security Science and Engineering Faculty Fellowship. Supported by the David and Lucile Packard Fellowship in science and engineering, the Henry Dreyfus Teacher-Scholar Award, and the Breakthroughs in Gerontology award from the American Federation for Aging Research. We thank Drs. W. M. Clemons, J. Chartron, and C. Suloway for the plasmids of SERP1, Sec61b_s, and cytochrome b5 and the Shan laboratory for helpful comments on the manuscript.

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Published - J._Biol._Chem.-2013-Jaru-Ampornpan-13431-45.pdf


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