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

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    Capraro, Dominique T.; Gosavi, Shachi; Roy, Melinda; Onuchic, José N.; Jennings, Patricia A.
    Date
    2012
    Abstract
    Interleukin-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.
    Citation
    Capraro, Dominique T., Gosavi, Shachi, Roy, Melinda, et al.. "Folding Circular Permutants of IL-1β: Route Selection Driven by Functional Frustration." PLoS ONE, 7, no. 6 (2012) Public Library of Science: e38512. http://dx.doi.org/10.1371/journal.pone.0038512.
    Published Version
    http://dx.doi.org/10.1371/journal.pone.0038512
    Type
    Journal article
    Publisher
    Public Library of Science
    Citable link to this page
    https://hdl.handle.net/1911/78898
    Rights
    This 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.
    Link to License
    https://creativecommons.org/licenses/by/4.0/
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    Managed by the Digital Scholarship Services at Fondren Library, Rice University
    Physical Address: 6100 Main Street, Houston, Texas 77005
    Mailing Address: MS-44, P.O.BOX 1892, Houston, Texas 77251-1892
    Site Map