M.Z.Cabail
et al.
(2015).
The insulin and IGF1 receptor kinase domains are functional dimers in the activated state.
Nat Commun,
6,
6406.
PubMed id: 25758790
DOI: 10.1038/ncomms7406
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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