Structure and functional analysis of the IGF-II/IGF2R interaction

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dc.contributor.authorBrown, J.
dc.contributor.authorDelaine, C.
dc.contributor.authorZaccheo, O.
dc.contributor.authorSiebold, C.
dc.contributor.authorGilbert, R.
dc.contributor.authorvan Boxel, G.
dc.contributor.authorDenley, A.
dc.contributor.authorWallace, J.
dc.contributor.authorHassan, A.
dc.contributor.authorForbes, B.
dc.contributor.authorJones, E.
dc.date.issued2008
dc.description.abstractEmbryonic 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.
dc.description.statementofresponsibilityJames 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
dc.identifier.citationEMBO Journal, 2008; 27(1):265-276
dc.identifier.doi10.1038/sj.emboj.7601938
dc.identifier.issn0261-4189
dc.identifier.issn1460-2075
dc.identifier.urihttp://hdl.handle.net/2440/43292
dc.language.isoen
dc.publisherNature Publishing Group
dc.rights© 2008 by the European Molecular Biology Organization
dc.source.urihttps://doi.org/10.1038/sj.emboj.7601938
dc.subjectgrowth factor receptor
dc.subjectIGF-II
dc.subjectIGF system
dc.subjectprotein crystallography
dc.subjecttumour suppression
dc.titleStructure and functional analysis of the IGF-II/IGF2R interaction
dc.typeJournal article
pubs.publication-statusPublished

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