title: Mechanism of an ATP-independent protein disaggregase: II. distinct molecular interactions drive multiple steps during aggregate disassembly.
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.
authors.affiliation: From the Division of Chemistry and Chemical Engineering and.
authors.forename: Peera
authors.initials: P
authors.lastname: Jaru-Ampornpan
authors.forename: Fu-Cheng
authors.initials: FC
authors.lastname: Liang
authors.forename: Alex
authors.initials: A
authors.lastname: Nisthal
authors.forename: Thang X
authors.initials: TX
authors.lastname: Nguyen
authors.forename: Pengcheng
authors.initials: P
authors.lastname: Wang
authors.forename: Kuang
authors.initials: K
authors.lastname: Shen
authors.forename: Steven L
authors.initials: SL
authors.lastname: Mayo
authors.forename: Shu-Ou
authors.initials: SO
authors.lastname: Shan
mesh_terms: D000595:Amino Acid Sequence; D017360:Arabidopsis; D029681:Arabidopsis Proteins / Q000737:chemistry*; D005454:Fluorescence Polarization; D057927:Hydrophobic and Hydrophilic Interactions; D007700:Kinetics; D045342:Light-Harvesting Protein Complexes / Q000737:chemistry* / Q000235:genetics; D008958:Models, Molecular; D018832:Molecular Chaperones / Q000737:chemistry; D008969:Molecular Sequence Data; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D055503:Protein Multimerization; D055550:Protein Stability; D020836:Protein Structure, Quaternary; D021122:Protein Subunits / Q000737:chemistry; D058767:Protein Unfolding; D017384:Sequence Deletion; D018271:Signal Recognition Particle / Q000737:chemistry*; D013379:Substrate Specificity; D013499:Surface Properties; D013816:Thermodynamics
chemical_list: D029681:Arabidopsis Proteins; D045342:Light-Harvesting Protein Complexes; D018832:Molecular Chaperones; D021122:Protein Subunits; D018271:Signal Recognition Particle; C568473:cpSRP43 protein, Arabidopsis
keywords: ATP-independent Disaggregase; Enzyme Mechanisms; Kinetics; Membrane Proteins; Molecular Chaperone; Mutagenesis Mechanisms; Protein Aggregation; Protein Biogenesis; Signal Recognition Particle