The Unique Cysteine Knot Regulates the Pleotropic Hormone Leptin

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dc.citation.firstpagee45654en_US
dc.citation.issueNumber9en_US
dc.citation.journalTitlePLoS Oneen_US
dc.citation.volumeNumber7en_US
dc.contributor.authorHaglund, Ellinoren_US
dc.contributor.authorSulkowska, Joanna I.en_US
dc.contributor.authorHe, Zhaoen_US
dc.contributor.authorFeng, Gen-Shengen_US
dc.contributor.authorJennings, Patricia A.en_US
dc.contributor.authorOnuchic, José N.en_US
dc.contributor.funderNational Science Foundationen_US
dc.contributor.funderNational Institutes of Healthen_US
dc.contributor.funderCancer Prevention and Research Institute of Texasen_US
dc.contributor.orgCenter for Theoretical Biological Physicsen_US
dc.date.accessioned2013-03-14T20:24:47Zen_US
dc.date.available2013-03-14T20:24:47Zen_US
dc.date.issued2012en_US
dc.description.abstractLeptin plays a key role in regulating energy intake/expenditure, metabolism and hypertension. It folds into a four-helix bundle that binds to the extracellular receptor to initiate signaling. Our work on leptin revealed a hidden complexity in the formation of a previously un-described, cysteine-knotted topology in leptin. We hypothesized that this unique topology could offer new mechanisms in regulating the protein activity. A combination of in silico simulation and in vitro experiments was used to probe the role of the knotted topology introduced by the disulphide-bridge on leptin folding and function. Our results surprisingly show that the free energy landscape is conserved between knotted and unknotted protein, however the additional complexity added by the knot formation is structurally important. Native state analyses led to the discovery that the disulphide-bond plays an important role in receptor binding and thus mediate biological activity by local motions on distal receptor-binding sites, far removed from the disulphide-bridge. Thus, the disulphide-bridge appears to function as a point of tension that allows dissipation of stress at a distance in leptin.en_US
dc.embargo.termsnoneen_US
dc.identifier.citationHaglund, Ellinor, Sulkowska, Joanna I., He, Zhao, et al.. "The Unique Cysteine Knot Regulates the Pleotropic Hormone Leptin." <i>PLoS One,</i> 7, no. 9 (2012) e45654. http://dx.doi.org/10.1371/journal.pone.0045654.en_US
dc.identifier.doihttp://dx.doi.org/10.1371/journal.pone.0045654en_US
dc.identifier.grantIDPHY-0822283 (National Science Foundation)en_US
dc.identifier.grantIDMCB-1051438 (National Science Foundation)en_US
dc.identifier.grantIDGM54038 (National Institutes of Health)en_US
dc.identifier.urihttps://hdl.handle.net/1911/70648en_US
dc.language.isoengen_US
dc.titleThe Unique Cysteine Knot Regulates the Pleotropic Hormone Leptinen_US
dc.typeJournal articleen_US
dc.type.dcmiTexten_US
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