Structural and Mechanistic Paradigm of Leptin Receptor Activation Revealed by Complexes with Wild-Type and Antagonist Leptins

Moharana, Kedar; Stahlberg, Henning; Tavernier, Jan; Ringler, Philippe; Peelman, Frank; Zabeau, Lennart; Savvides, Savvas

doi:10.1016/j.str.2014.04.012

Journal Article

PUBDB-2015-00995

Structural and Mechanistic Paradigm of Leptin Receptor Activation Revealed by Complexes with Wild-Type and Antagonist Leptins

Moharana, K. (Corresponding Author)>Extern* ; Zabeau, L. ; Peelman, F. ; Ringler, P. ; Stahlberg, H. ; Tavernier, J. ; Savvides, S.>Extern*

2014
Elsevier Science London [u.a.]

Structure 22(6), 866 - 877 (2014) [10.1016/j.str.2014.04.012]

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Please use a persistent id in citations: doi:10.1016/j.str.2014.04.012

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

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