Structure and functional analysis of the IGF-II/IGF2R interaction
Date
2008
Authors
Brown, J.
Delaine, C.
Zaccheo, O.
Siebold, C.
Gilbert, R.
van Boxel, G.
Denley, A.
Wallace, J.
Hassan, A.
Forbes, B.
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Journal article
Citation
EMBO Journal, 2008; 27(1):265-276
Statement of Responsibility
James Brown, Carlie Delaine, Oliver J Zaccheo, Christian Siebold, Robert J Gilbert, Gijs van Boxel, Adam Denley, John C Wallace, A Bassim Hassan, Briony E Forbes and E Yvonne Jones
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Abstract
Embryonic development and normal growth require exquisite control of insulin-like growth factors (IGFs). In mammals the extracellular region of the cation-independent mannose-6-phosphate receptor has gained an IGF-II-binding function and is termed type II IGF receptor (IGF2R). IGF2R sequesters IGF-II; imbalances occur in cancers and IGF2R is implicated in tumour suppression. We report crystal structures of IGF2R domains 11–12, 11–12–13–14 and domains 11–12–13/IGF-II complex. A distinctive juxtaposition of these domains provides the IGF-II-binding unit, with domain 11 directly interacting with IGF-II and domain 13 modulating binding site flexibility. Our complex shows that Phe19 and Leu53 of IGF-II lock into a hydrophobic pocket unique to domain 11 of mammalian IGF2Rs. Mutagenesis analyses confirm this IGF-II 'binding-hotspot', revealing that IGF-binding proteins and IGF2R have converged on the same high-affinity site.
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© 2008 by the European Molecular Biology Organization