Altered Backbone and Side-Chain Interactions Result in Route Heterogeneity during the Folding of Interleukin-1b (IL-1b)

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dc.citation.firstpage975en_US
dc.citation.journalTitleBiophysical Journalen_US
dc.citation.lastpage983en_US
dc.citation.volumeNumber105en_US
dc.contributor.authorCapraro, Dominique T.en_US
dc.contributor.authorLammert, Heikoen_US
dc.contributor.authorHeidary, David K.en_US
dc.contributor.authorRoy, Melindaen_US
dc.contributor.authorGross, Larry A.en_US
dc.contributor.authorOnuchic, José N.en_US
dc.contributor.authorJennings, Patricia A.en_US
dc.contributor.orgCenter for Theoretical Biological Physicsen_US
dc.date.accessioned2013-08-30T20:18:07Z
dc.date.available2014-08-31T05:10:03Z
dc.date.issued2013-08en_US
dc.description.abstractDeletion of the b-bulge trigger-loop results in both a switch in the preferred folding route, from the functional loop packing folding route to barrel closure, as well as conversion of the agonist activity of IL-1b into antagonist activity. Conversely, circular permutations of IL-1b conserve the functional folding route as well as the agonist activity. These two extremes in the folding-functional interplay beg the question of whether mutations in IL-1b would result in changes in the populations of heterogeneous folding routes and the signaling activity. A series of topologically equivalent water-mediated b-strand bridging interactions within the pseudosymmetric b-trefoil fold of IL-1b highlight the backbone water interactions that stabilize the secondary and tertiary structure of the protein. Additionally, conserved aromatic residues lining the central cavity appear to be essential for both stability and folding. Here, we probe these protein backbone-water molecule and side chain-side chain interactions and the role they play in the folding mechanism of this geometrically stressed molecule. We used folding simulations with structure-based models, as well as a series of folding kinetic experiments to examine the effects of the F42W core mutation on the folding landscape of IL-1b. This mutation alters water-mediated backbone interactions essential for maintaining the trefoil fold. Our results clearly indicate that this perturbation in the primary structure alters a structural water interaction and consequently modulates the population of folding routes accessed during folding and signaling activity.en_US
dc.embargo.terms1 yearen_US
dc.identifier.citationCapraro, Dominique T., Lammert, Heiko, Heidary, David K., et al.. "Altered Backbone and Side-Chain Interactions Result in Route Heterogeneity during the Folding of Interleukin-1b (IL-1b)." <i>Biophysical Journal,</i> 105, (2013) Biophysical Society: 975-983. http://dx.doi.org/10.1016/j.bpj.2013.06.019.
dc.identifier.doihttp://dx.doi.org/10.1016/j.bpj.2013.06.019en_US
dc.identifier.urihttps://hdl.handle.net/1911/71865
dc.language.isoengen_US
dc.publisherBiophysical Society
dc.rightsArticle is made available in accordance with the publisher's policy and may be subject to US copyright law. Please refer to the publisher's site for terms of use.
dc.titleAltered Backbone and Side-Chain Interactions Result in Route Heterogeneity during the Folding of Interleukin-1b (IL-1b)en_US
dc.typeJournal articleen_US
dc.type.dcmiTexten_US
dc.type.publicationpublisher versionen_US
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