A proline switch explains kinetic heterogeneity in a coupled folding and binding reaction
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Date
2018-08-20
Publication Type
Journal Article
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yes
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Abstract
The interactions of intrinsically disordered proteins (IDPs) with their molecular targets are essential for the regulation of many cellular processes. IDPs can perform their functions while disordered, and they may fold to structured conformations on binding. Here we show that the cis/trans isomerization of peptidyl−prolyl bonds can have a pronounced effect on the interactions of IDPs. By single-molecule spectroscopy, we identify a conserved proline residue in NCBD (the nuclear-coactivator binding domain of CBP) whose cis/trans isomerization in the unbound state modulates the association and dissociation rates with its binding partner, ACTR. As a result, NCBD switches on a time scale of tens of seconds between two populations that differ in their affinities to ACTR by about an order of magnitude. Molecular dynamics simulations indicate as a cause reduced packing of the complex for the cis isomer. Peptidyl-prolyl cis/trans isomerization may be an important previously unidentified mechanism for regulating IDP interactions.
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published
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Journal / series
Volume
9
Pages / Article No.
3332
Publisher
Nature
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Edition / version
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Subject
Biophysical chemistry; Biophysics; Kinetics; Reaction kinetics and dynamics; Molecular biophysics
Organisational unit
02207 - Functional Genomics Center Zurich / Functional Genomics Center Zurich
Notes
Funding
170976 - Role of Disordered Regions in RNA-Binding Proteins for Function and Pathology (SNF)