Journal
JOURNAL OF MOLECULAR BIOLOGY
Volume 434, Issue 5, Pages -Publisher
ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD
DOI: 10.1016/j.jmb.2022.167458
Keywords
insulin; insulin receptor; insulin receptor dimer; insulin receptor dynamics; insulin receptor sites
Categories
Funding
- Innovation Fund Denmark [7038-00013B]
- Novo Nordisk Foundation [NNF0054875]
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Insulin regulates glucose homeostasis by binding and activating the insulin receptor in an asymmetric manner. This study reveals how insulin binds at two distinct sites and disrupts the autoinhibited state, stabilizing the active state of the receptor.
Insulin regulates glucose homeostasis via binding and activation of the insulin receptor dimer at two distinct pairs of binding sites 1 and 2. Here, we present cryo-EM studies of full-length human insulin receptor (hIR) in an active state obtained at non-saturating, physiologically relevant insulin conditions. Insulin binds asymmetrically to the receptor under these conditions, occupying up to three of the four possible binding sites. Deletion analysis of the receptor together with site specific peptides and insulin analogs used in binding studies show that both sites 1 and 2 are required for high insulin affinity. We identify a homotypic interaction of the fibronectin type III domain (FnIII-3) of IR resulting in tight interaction of membrane proximal domains of the active, asymmetric receptor dimer. Our results show how insulin binding at two distinct types of sites disrupts the autoinhibited apo-IR dimer and stabilizes the active dimer. We propose an insulin binding and activation mechanism, which is sequential, exhibits negative cooperativity, and is based on asymmetry at physiological insulin concentrations with one to three insulin molecules activating IR.(c) 2022 The Author(s). Published by Elsevier Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
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