Structure and functional analysis of the IGF-II/IGF2R interaction |
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Authors: | Brown James Delaine Carlie Zaccheo Oliver J Siebold Christian Gilbert Robert J van Boxel Gijs Denley Adam Wallace John C Hassan A Bassim Forbes Briony E Jones E Yvonne |
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Affiliation: | Cancer Research UK Receptor Structure Research Group, Division of Structural Biology, Wellcome Trust Centre for Human Genetics, University of Oxford, Headington, Oxford, UK. |
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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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Keywords: | growth factor receptor IGF-II IGF system protein crystallography tumour suppression |
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