title: The unique cysteine knot regulates the pleotropic hormone leptin.
abstract: Leptin 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.
authors.affiliation: Department of Chemistry and Biochemistry and Center for theoretical Biological Physics (CTBP), University of California San Diego, La Jolla, CA, USA.
authors.forename: Ellinor
authors.initials: E
authors.lastname: Haglund
authors.forename: Joanna I
authors.initials: JI
authors.lastname: Sułkowska
authors.forename: Zhao
authors.initials: Z
authors.lastname: He
authors.forename: Gen-Sheng
authors.initials: GS
authors.lastname: Feng
authors.forename: Patricia A
authors.initials: PA
authors.lastname: Jennings
authors.forename: José N
authors.initials: JN
authors.lastname: Onuchic
mesh_terms: D003545:Cysteine / Q000502:physiology*; D006801:Humans; D007700:Kinetics; D020738:Leptin / Q000737:chemistry / Q000502:physiology*; D061986:MCF-7 Cells; D008958:Models, Molecular; D010084:Oxidation-Reduction; D015398:Signal Transduction
chemical_list: D020738:Leptin; D003545:Cysteine