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Coupled Folding and Binding of the Disordered Protein PUMA Does Not Require Particular Residual Structure

[Image: see text] Many cellular proteins are ‘disordered’ in isolation. A subset of these intrinsically disordered proteins (IDPs) can, upon binding another molecule, fold to a well-defined three-dimensional structure. In the structurally heterogeneous, unbound ensemble of these IDPs, conformations...

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Autores principales: Rogers, Joseph M., Wong, Chi T., Clarke, Jane
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Chemical Society 2014
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4017604/
https://www.ncbi.nlm.nih.gov/pubmed/24654952
http://dx.doi.org/10.1021/ja4125065
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author Rogers, Joseph M.
Wong, Chi T.
Clarke, Jane
author_facet Rogers, Joseph M.
Wong, Chi T.
Clarke, Jane
author_sort Rogers, Joseph M.
collection PubMed
description [Image: see text] Many cellular proteins are ‘disordered’ in isolation. A subset of these intrinsically disordered proteins (IDPs) can, upon binding another molecule, fold to a well-defined three-dimensional structure. In the structurally heterogeneous, unbound ensemble of these IDPs, conformations are likely to exist that, in part, resemble the final bound form. It has been suggested that these conformations, displaying ‘residual structure’, could be important for the mechanism of such coupled folding and binding reactions. PUMA, of the BCL-2 family, is an IDP in isolation but will form a single, contiguous α-helix upon binding the folded protein MCL-1. Using the helix-breaking residue proline, we systematically target each potential turn of helix of unbound PUMA and assess the binding to MCL-1 using time-resolved stopped-flow techniques. All proline-containing mutants bound, and although binding was weaker than the wild-type protein, association rate constants were largely unaffected. We conclude that population of particular residual structure, containing a specific helical turn, is neither required for the binding nor for fast association of PUMA and MCL-1.
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spelling pubmed-40176042014-05-12 Coupled Folding and Binding of the Disordered Protein PUMA Does Not Require Particular Residual Structure Rogers, Joseph M. Wong, Chi T. Clarke, Jane J Am Chem Soc [Image: see text] Many cellular proteins are ‘disordered’ in isolation. A subset of these intrinsically disordered proteins (IDPs) can, upon binding another molecule, fold to a well-defined three-dimensional structure. In the structurally heterogeneous, unbound ensemble of these IDPs, conformations are likely to exist that, in part, resemble the final bound form. It has been suggested that these conformations, displaying ‘residual structure’, could be important for the mechanism of such coupled folding and binding reactions. PUMA, of the BCL-2 family, is an IDP in isolation but will form a single, contiguous α-helix upon binding the folded protein MCL-1. Using the helix-breaking residue proline, we systematically target each potential turn of helix of unbound PUMA and assess the binding to MCL-1 using time-resolved stopped-flow techniques. All proline-containing mutants bound, and although binding was weaker than the wild-type protein, association rate constants were largely unaffected. We conclude that population of particular residual structure, containing a specific helical turn, is neither required for the binding nor for fast association of PUMA and MCL-1. American Chemical Society 2014-03-21 2014-04-09 /pmc/articles/PMC4017604/ /pubmed/24654952 http://dx.doi.org/10.1021/ja4125065 Text en Copyright © 2014 American Chemical Society Terms of Use CC-BY (http://pubs.acs.org/page/policy/authorchoice_ccby_termsofuse.html)
spellingShingle Rogers, Joseph M.
Wong, Chi T.
Clarke, Jane
Coupled Folding and Binding of the Disordered Protein PUMA Does Not Require Particular Residual Structure
title Coupled Folding and Binding of the Disordered Protein PUMA Does Not Require Particular Residual Structure
title_full Coupled Folding and Binding of the Disordered Protein PUMA Does Not Require Particular Residual Structure
title_fullStr Coupled Folding and Binding of the Disordered Protein PUMA Does Not Require Particular Residual Structure
title_full_unstemmed Coupled Folding and Binding of the Disordered Protein PUMA Does Not Require Particular Residual Structure
title_short Coupled Folding and Binding of the Disordered Protein PUMA Does Not Require Particular Residual Structure
title_sort coupled folding and binding of the disordered protein puma does not require particular residual structure
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4017604/
https://www.ncbi.nlm.nih.gov/pubmed/24654952
http://dx.doi.org/10.1021/ja4125065
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