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

Jaru-Ampornpan, Peera and Liang, Fu-Cheng and Nisthal, Alex and Nguyen, Thang X. and Wang, Pengcheng and Shen, Kuang and Mayo, Steven L. and Shan, Shu-ou (2013) Mechanism of an ATP-independent Protein Disaggregase. II. Distinct Molecular Interactions Drive Multiple Steps During Aggregate Disassembly. Journal of Biological Chemistry, 288 (19). pp. 13431-13445. ISSN 0021-9258. PMCID PMC3650381. http://resolver.caltech.edu/CaltechAUTHORS:20130621-133910862

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Abstract

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.


Item Type:Article
Related URLs:
URLURL TypeDescription
http://www.jbc.org/content/288/19/13431PublisherArticle
http://dx.doi.org/10.1074/jbc.M113.462861DOIArticle
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3650381/PubMed CentralArticle
ORCID:
AuthorORCID
Shan, Shu-ou0000-0002-6526-1733
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.
Funders:
Funding AgencyGrant Number
National Security Science and Engineering Faculty FellowshipUNSPECIFIED
David and Lucile Packard FoundationUNSPECIFIED
Camille and Henry Dreyfus FoundationUNSPECIFIED
American Federation for Aging ResearchUNSPECIFIED
Subject Keywords:Enzyme Mechanisms; Kinetics; Molecular Chaperone; Mutagenesis Mechanisms; Protein Aggregation; ATP-independent Disaggregase; Membrane Proteins; Protein Biogenesis; Signal Recognition Particle.
PubMed Central ID:PMC3650381
Record Number:CaltechAUTHORS:20130621-133910862
Persistent URL:http://resolver.caltech.edu/CaltechAUTHORS:20130621-133910862
Official Citation:Jaru-Ampornpan, P., Liang, F.-C., Nisthal, A., Nguyen, T. X., Wang, P., Shen, K., Mayo, S. L., and Shan, S. (2013) Mechanism of an ATPindependent protein disaggregase: II. Distinct molecular interactions drive multiple steps during aggregate disassembly. J. Biol. Chem. 288, 13431–13445
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:39030
Collection:CaltechAUTHORS
Deposited By: John Wade
Deposited On:21 Jun 2013 21:26
Last Modified:30 Jan 2017 23:36

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