Folding Circular Permutants of IL-1β: Route Selection Driven by Functional Frustration

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dc.citation.firstpagee38512
dc.citation.issueNumber6
dc.citation.journalTitlePLoS ONE
dc.citation.volumeNumber7
dc.contributor.authorCapraro, Dominique T.
dc.contributor.authorGosavi, Shachi
dc.contributor.authorRoy, Melinda
dc.contributor.authorOnuchic, José N.
dc.contributor.authorJennings, Patricia A.
dc.contributor.orgCenter for Theoretical Biological Physics
dc.date.accessioned2015-01-06T19:20:34Z
dc.date.available2015-01-06T19:20:34Z
dc.date.issued2012
dc.description.abstractInterleukin-1β (IL-1β) is the cytokine crucial to inflammatory and immune response. Two dominant routes are populated in the folding to native structure. These distinct routes are a result of the competition between early packing of the functional loops versus closure of the β-barrel to achieve efficient folding and have been observed both experimentally and computationally. Kinetic experiments on the WT protein established that the dominant route is characterized by early packing of geometrically frustrated functional loops. However, deletion of one of the functional loops, the β-bulge, switches the dominant route to an alternative, yet, as accessible, route, where the termini necessary for barrel closure form first. Here, we explore the effect of circular permutation of the WT sequence on the observed folding landscape with a combination of kinetic and thermodynamic experiments. Our experiments show that while the rate of formation of permutant protein is always slower than that observed for the WT sequence, the region of initial nucleation for all permutants is similar to that observed for the WT protein and occurs within a similar timescale. That is, even permutants with significant sequence rearrangement in which the functional-nucleus is placed at opposing ends of the polypeptide chain, fold by the dominant WT “functional loop-packing route”, despite the entropic cost of having to fold the N- and C- termini early. Taken together, our results indicate that the early packing of the functional loops dominates the folding landscape in active proteins, and, despite the entropic penalty of coalescing the termini early, these proteins will populate an entropically unfavorable route in order to conserve function. More generally, circular permutation can elucidate the influence of local energetic stabilization of functional regions within a protein, where topological complexity creates a mismatch between energetics and topology in active proteins.
dc.identifier.citationCapraro, Dominique T., Gosavi, Shachi, Roy, Melinda, et al.. "Folding Circular Permutants of IL-1β: Route Selection Driven by Functional Frustration." <i>PLoS ONE,</i> 7, no. 6 (2012) Public Library of Science: e38512. http://dx.doi.org/10.1371/journal.pone.0038512.
dc.identifier.doihttp://dx.doi.org/10.1371/journal.pone.0038512
dc.identifier.urihttps://hdl.handle.net/1911/78898
dc.language.isoeng
dc.publisherPublic Library of Science
dc.rightsThis is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/
dc.titleFolding Circular Permutants of IL-1β: Route Selection Driven by Functional Frustration
dc.typeJournal article
dc.type.dcmiText
dc.type.publicationpublisher version
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