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Chaperone action of a cofactor in protein folding.

ABSTRACT: Previously, we have reported that ATP accelerates the folding and unfolding of Escherichia coli glyceraldehyde-3-phosphate dehydrogenase (GAPDH), which is a glycolytic enzyme utilizing NAD⁺ as a cofactor. Because ATP and NAD⁺ share the ADP moiety, we hypothesized that NAD⁺ also accelerates the folding of GAPDH and that the common structural motif between ATP and NAD⁺ is responsible for the chaperone activity. After confirming that NAD⁺ indeed accelerates the folding of GAPDH, we examined the chaperone activity of the structural fragments of NAD⁺ (ADP, AMP, adenosine, and nicotinamide monophosphate). Our finding showed that ADP and AMP significantly speed up the folding of GAPDH, while adenosine and nicotinamide monophosphate do not. ADP and AMP also dramatically speed up the unfolding of GAPDH by selectively stabilizing a transition state in which GAPDH has a partially unfolded conformation. Similar to the previously reported effect of ATP on the equilibrium unfolding of GAPDH, a partially unfolded intermediate also accumulates in the presence of ADP and AMP. Based on the effect of the structural fragments of NAD⁺ on the folding of GAPDH, we identified that AMP is the structural determinant of the chaperone activity of ATP and NAD⁺ . Also, we propose a plausible model to explain how NAD⁺ accelerates the folding of GAPDH through a stepwise development of molecular interactions with the protein.

SUBMITTER: Chen C

PROVIDER: S-EPMC7314391 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

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Chaperone action of a cofactor in protein folding.

Chen Chen C Park Chiwook C

Protein science : a publication of the Protein Society 20200608 7

Previously, we have reported that ATP accelerates the folding and unfolding of Escherichia coli glyceraldehyde-3-phosphate dehydrogenase (GAPDH), which is a glycolytic enzyme utilizing NAD+ as a cofactor. Because ATP and NAD+ share the ADP moiety, we hypothesized that NAD+ also accelerates the folding of GAPDH and that the common structural motif between ATP and NAD+ is responsible for the chaperone activity. After confirming that NAD+ indee ...[more]

PMID: 32385904

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Project description:Molecular chaperones, a family of proteins of which Hsp90 and Hsp70 are integral members, form an essential machinery to maintain healthy proteomes by controlling the folding and activation of a plethora of substrate client proteins. This is achieved through cycles in which Hsp90 and Hsp70, regulated by task-specific co-chaperones, process ATP and become part of a complex network that undergoes extensive compositional and conformational variations. Despite impressive advances in structural knowledge, the mechanisms that regulate the dynamics of functional assemblies, their response to nucleotides, and their relevance for client remodeling are still elusive. Here, we focus on the glucocorticoid receptor (GR):Hsp90:Hsp70:co-chaperone Hop client-loading and the GR:Hsp90:co-chaperone p23 client-maturation complexes, key assemblies in the folding cycle of glucocorticoid receptor (GR), a client strictly dependent upon Hsp90/Hsp70 for activity. Using a combination of molecular dynamics simulation approaches, we unveil with unprecedented detail the mechanisms that underpin function in these chaperone machineries. Specifically, we dissect the processes by which the nucleotide-encoded message is relayed to the client and how the distinct partners of the assemblies cooperate to (pre)organize partially folded GR during Loading and Maturation. We show how different ligand states determine distinct dynamic profiles for the functional interfaces defining the interactions in the complexes and modulate their overall flexibility to facilitate progress along the chaperone cycle. Finally, we also show that the GR regions engaged by the chaperone machinery display peculiar energetic signatures in the folded state, which enhance the probability of partial unfolding fluctuations. From these results, we propose a model where a dynamic cross-talk emerges between the chaperone dynamics states and remodeling of client-interacting regions. This factor, coupled to the highly dynamic nature of the assemblies and the conformational heterogeneity of their interactions, provides the basis for regulating the functions of distinct assemblies during the chaperoning cycle.

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Chaperone action of a cofactor in protein folding.

Publications

Chaperone action of a cofactor in protein folding.

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