Mechanism of the small ATP-independent chaperone Spy is substrate specific

Mitra, Rishav; Gadkari, Varun V.; Meinen, Ben A.; Mierlo, C.P.M. van; Ruotolo, Brandon T.; Bardwell, James C.A.

doi:10.1038/s41467-021-21120-8

Cited by 26 publications

(19 citation statements)

References 60 publications

(47 reference statements)

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“…For understanding the process better, kinetic information is important. Recent studies focusing on the binding kinetics between the chaperone and client proteins [ 13 , 15 , 16 , 17 , 63 , 64 ] have revealed that the chaperone–client complex is dynamic and mediated by fast binding–release exchange [ 16 , 54 ]. Furthermore, the foldase and holdase activities of molecular chaperones are related to the binding kinetics between the chaperone and client protein and to the folding speed of the client protein [ 16 ].…”

Section: Kinetic Studies For Molecular Chaperones and Client Proteinsmentioning

confidence: 99%

Structural and Kinetic Views of Molecular Chaperones in Multidomain Protein Folding

Kawagoe

Ishimori

Saio

2022

IJMS

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Despite recent developments in protein structure prediction, the process of the structure formation, folding, remains poorly understood. Notably, folding of multidomain proteins, which involves multiple steps of segmental folding, is one of the biggest questions in protein science. Multidomain protein folding often requires the assistance of molecular chaperones. Molecular chaperones promote or delay the folding of the client protein, but the detailed mechanisms are still unclear. This review summarizes the findings of biophysical and structural studies on the mechanism of multidomain protein folding mediated by molecular chaperones and explains how molecular chaperones recognize the client proteins and alter their folding properties. Furthermore, we introduce several recent studies that describe the concept of kinetics–activity relationships to explain the mechanism of functional diversity of molecular chaperones.

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Section: Kinetic Studies For Molecular Chaperones and Client Proteinsmentioning

confidence: 99%

Structural and Kinetic Views of Molecular Chaperones in Multidomain Protein Folding

Kawagoe

Ishimori

Saio

2022

IJMS

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“…Similar growth retardation was observed in cells expressing Spy D26K , but not in cells expressing Spy D26E . It has been shown that the folding rate of clients bound to Spy is much slower compared to their spontaneous folding in solution 21 , 32 , 33 . Consistent with this, we observed a similar inhibitory effect of Spy on the folding rate of another client, α-LA, and noted that the variant Spy 29-138 retarded α-LA folding more severely than the Spy wild type (Supplementary Fig.…”

Section: Discussionmentioning

confidence: 99%

Insights into the client protein release mechanism of the ATP-independent chaperone Spy

Xue

et al. 2022

Nat Commun

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Molecular chaperones play a central role in regulating protein homeostasis, and their active forms often contain intrinsically disordered regions (IDRs). However, how IDRs impact chaperone action remains poorly understood. Here, we discover that the disordered N terminus of the prototype chaperone Spy facilitates client release. With NMR spectroscopy and molecular dynamics simulations, we find that the N terminus can bind transiently to the client-binding cavity of Spy primarily through electrostatic interactions mediated by the N-terminal D26 residue. This intramolecular interaction results in a dynamic competition of the N terminus with the client for binding to Spy, which promotes client discharge. Our results reveal the mechanism by which Spy releases clients independent of energy input, thus enriching the current knowledge on how ATP-independent chaperones release their clients and highlighting the importance of synergy between IDRs and structural domains in regulating protein function.

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“…As opposed to that, opp operon (oppABCDF) that encodes the components in a polyamine-induced oligopeptide ABC transport system is upregulated for the transport of hydrophilic substances to compensate for the hydrophobic pressure exerted by alcohols [137,138]. Genes responsible for response to heat shock and extracytoplasmic stress (cpx regulon) are upregulated, and periplasmic chaperone Spy is encoded to respond to protein misfolding activity [139][140][141][142]. Increased isobutanol tolerance of C. acetobutylicum is also conferred to overexpression of genes related to heat shock [139,143].…”

Section: Stress Response Systemmentioning

confidence: 99%

A Critical Review on the Economically Feasible and Sustainable Poly(3-Hydroxybutyrate-co-3-hydroxyvalerate) Production from Alkyl Alcohols

2022

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Poly(3-hydroxybutyrate-co-3-hydroxyvalerate) (P(3HB-co-3HV)) is the most studied short-chain-length polyhydroxyalkanoates (PHA) with high application importance in various fields. The domination of high-cost propionate and valerate over other 3-hydroxyvalerate (3HV) precursors owing to their wide preference among PHA-producing bacteria has hindered the development of diverse production processes. As alkyl alcohols are mainly produced from inexpensive starting materials through oxo synthesis, they contribute a cost-effective advantage over propionate and valerate. Moreover, alkyl alcohols can be biosynthesized from natural substrates and organic wastes. Despite their great potential, their toxicity to most PHA-producing bacteria has been the major drawback for their wide implementation as 3HV precursors for decades. Although the standard PHA-producing bacteria Cupriavidus necator showed promising alcohol tolerance, the 3HV yield was discouraging. Continuous discovery of alkyl alcohols-utilizing PHA-producing bacteria has enabled broader choices in 3HV precursor selection for diverse P(3HB-co-3HV) production processes with higher economic feasibility. Besides continuous effort in searching for promising wild-type strains, genetic engineering to construct promising recombinant strains based on the understanding of the mechanisms involved in alkyl alcohols toxicity and tolerance is an alternative approach. However, more studies are required for techno-economic assessment to analyze the economic performance of alkyl alcohol-based production compared to that of organic acids.

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Mechanism of the small ATP-independent chaperone Spy is substrate specific

Cited by 26 publications

References 60 publications

Structural and Kinetic Views of Molecular Chaperones in Multidomain Protein Folding

Structural and Kinetic Views of Molecular Chaperones in Multidomain Protein Folding

Insights into the client protein release mechanism of the ATP-independent chaperone Spy

A Critical Review on the Economically Feasible and Sustainable Poly(3-Hydroxybutyrate-co-3-hydroxyvalerate) Production from Alkyl Alcohols

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