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Structural and mechanistic paradigm of leptin receptor activation revealed by complexes with wild-type and antagonist leptins

Moharana, Kedar and Zabeau, Lennart and Peelman, Frank and Ringler, Philippe and Stahlberg, Henning and Tavernier, Jan and Savvides, Savvas N.. (2014) Structural and mechanistic paradigm of leptin receptor activation revealed by complexes with wild-type and antagonist leptins. Structure, Vol. 22, H. 6. pp. 866-877.

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Official URL: http://edoc.unibas.ch/dok/A6329113

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Abstract

Leptin activates its cognate receptor (LR) to regulate body weight and metabolically costly processes, such as reproduction and immune responses. Despite such benevolent pleiotropy, leptin-mediated signaling has been implicated in autoimmune diseases and breast cancer, thereby rejuvenating interest in leptin antagonism. We present comparative biochemical and structural studies of the LR ectodomain (LRecto) in complex with wild-type and antagonist leptin variants. We show that high-affinity binding of leptin to the cytokine receptor homology 2 domain of LRecto primes interactions with the Ig-domain (LRIg) of another leptin-bound LRecto to establish a quaternary assembly. In contrast, antagonist leptin variants carrying mutations at the LRIg binding site only enable binary complexes with LRecto. Acetylation of free cysteines in LRecto also abrogates quaternary complexes, suggesting a functional role for intrareceptor disulfides. We propose a revised conceptual framework for LR activation whereby leptin activates predimerized LR at the cell surface to seed higher order complexes with 4:4 stoichiometry.
Faculties and Departments:05 Faculty of Science > Departement Biozentrum > Structural Biology & Biophysics > Structural Biology (Stahlberg)
UniBasel Contributors:Stahlberg, Henning
Item Type:Article, refereed
Article Subtype:Research Article
Bibsysno:Link to catalogue
Publisher:Current Biology
ISSN:0969-2126
Note:Publication type according to Uni Basel Research Database: Journal article
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Last Modified:06 Feb 2015 09:58
Deposited On:06 Feb 2015 09:58

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