TY  - JOUR
AU  - Moharana, Kedar
AU  - Zabeau, Lennart
AU  - Peelman, Frank
AU  - Ringler, Philippe
AU  - Stahlberg, Henning
AU  - Tavernier, Jan
AU  - Savvides, Savvas
TI  - Structural and Mechanistic Paradigm of Leptin Receptor Activation Revealed by Complexes with Wild-Type and Antagonist Leptins
JO  - Structure
VL  - 22
IS  - 6
SN  - 0969-2126
CY  - London [u.a.]
PB  - Elsevier Science
M1  - PUBDB-2015-00995
SP  - 866 - 877
PY  - 2014
AB  - 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
LB  - PUB:(DE-HGF)16
UR  - <Go to ISI:>//WOS:000338206200009
C6  - pmid:24882746
DO  - DOI:10.1016/j.str.2014.04.012
UR  - https://bib-pubdb1.desy.de/record/206531
ER  -