The insulin and IGF1 receptor kinase domains are functional dimers in the activated state

Nature Communications
M Zulema CabailW T Miller

Abstract

The insulin receptor (IR) and insulin-like growth factor-1 receptor (IGF1R) are highly related receptor tyrosine kinases with a disulfide-linked homodimeric architecture. Ligand binding to the receptor ectodomain triggers tyrosine autophosphorylation of the cytoplasmic domains, which stimulates catalytic activity and creates recruitment sites for downstream signalling proteins. Whether the two phosphorylated tyrosine kinase domains within the receptor dimer function independently or cooperatively to phosphorylate protein substrates is not known. Here we provide crystallographic, biophysical and biochemical evidence demonstrating that the phosphorylated kinase domains of IR and IGF1R form a specific dimeric arrangement involving an exchange of the juxtamembrane region proximal to the kinase domain. In this dimer, the active position of α-helix C in the kinase N lobe is stabilized, which promotes downstream substrate phosphorylation. These studies afford a novel strategy for the design of small-molecule IR agonists as potential therapeutic agents for type 2 diabetes.

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Citations

Jan 23, 2016·Scientific Reports·Jitka VikováJiří Jiráček
Jul 6, 2016·Frontiers in Endocrinology·Hossein Mohammadiarani, Harish Vashisth
Jul 9, 2016·BMC Biochemistry·M Zulema CabailW Todd Miller
Oct 8, 2016·Growth Hormone & IGF Research : Official Journal of the Growth Hormone Research Society and the International IGF Research Society·Briony E Forbes
Sep 18, 2016·Cold Spring Harbor Perspectives in Biology·Søren T ChristensenLotte B Pedersen
Sep 22, 2017·International Journal of Molecular Sciences·Zhihua Du, Vladimir N Uversky
Feb 18, 2018·The Journal of Cell Biology·Theresia GutmannÜnal Coskun
Oct 26, 2018·Nature Communications·Felix WeisMichael C Lawrence
Aug 26, 2020·Proceedings of the National Academy of Sciences of the United States of America·Douglas SammonBirgit Leitinger
Oct 17, 2019·The Journal of Biological Chemistry·Eleonora V ShtykovaAlexander G Petrenko
Nov 8, 2019·Protein Science : a Publication of the Protein Society·Mehul K JoshiCarol Beth Post
Jan 17, 2020·International Journal of Molecular Sciences·Christian SchwiebertLutz Schomburg
Sep 3, 2020·Growth Hormone & IGF Research : Official Journal of the Growth Hormone Research Society and the International IGF Research Society·Nasima BanoMohd Jamal Dar
Apr 28, 2021·Chemistry : a European Journal·Lucía TapiaIgnacio Alfonso
May 17, 2021·Molecular Metabolism·Michael C Lawrence

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