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A structurally heterogeneous transition state underlies coupled binding and folding of disordered proteins
Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
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Number of Authors: 62019 (English)In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 294, no 4, p. 1230-1239Article in journal (Refereed) Published
Abstract [en]

Many intrinsically disordered proteins (IDPs) attain a well-defined structure in a coupled folding and binding reaction with another protein. Such reactions may involve early to late formation of different native structural regions along the reaction pathway. To obtain insights into the transition state for a coupled binding and folding reaction, we performed restrained molecular dynamics simulations using previously determined experimental binding phi(b) values of the interaction between two IDP domains: the activation domain from the p160 transcriptional co-activator for thyroid hormone and retinoid receptors (ACTR) and the nuclear co-activator binding domain (NCBD) of CREB-binding protein, each forming three well-defined alpha-helices upon binding. These simulations revealed that both proteins are largely disordered in the transition state for complex formation, except for two helices, one from each domain, that display a native-like structure. The overall transition state structure was extended and largely dynamic with many weakly populated contacts. To test the transition state model, we combined site-directed mutagenesis with kinetic experiments, yielding results consistent with overall diffuse interactions and formation of native intramolecular interactions in the third NCBD helix during the binding reaction. Our findings support the view that the transition state and, by inference, any encounter complex in coupled binding and folding reactions are structurally heterogeneous and largely independent of specific interactions. Furthermore, experimental phi(b) values and Bronsted plots suggested that the transition state is globally robust with respect to most mutations but can display more native-like features for some highly destabilizing mutations, possibly because of Hammond behavior or ground-state effects.

Place, publisher, year, edition, pages
2019. Vol. 294, no 4, p. 1230-1239
Keywords [en]
intrinsically disordered protein, pre-steady-state kinetics, protein folding, protein-protein interaction, molecular dynamics
National Category
Biological Sciences
Identifiers
URN: urn:nbn:se:su:diva-166791DOI: 10.1074/jbc.RA118.005854ISI: 000457879500014PubMedID: 30514761OAI: oai:DiVA.org:su-166791DiVA, id: diva2:1295521
Available from: 2019-03-12 Created: 2019-03-12 Last updated: 2019-03-12Bibliographically approved

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