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https://hdl.handle.net/2440/43292
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Type: | Journal article |
Title: | Structure and functional analysis of the IGF-II/IGF2R interaction |
Author: | Brown, J. Delaine, C. Zaccheo, O. Siebold, C. Gilbert, R. van Boxel, G. Denley, A. Wallace, J. Hassan, A. Forbes, B. Jones, E. |
Citation: | The EMBO Journal, 2008; 27(1):265-276 |
Publisher: | Nature Publishing Group |
Issue Date: | 2008 |
ISSN: | 0261-4189 1460-2075 |
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 |
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. |
Keywords: | growth factor receptor IGF-II IGF system protein crystallography tumour suppression |
Rights: | © 2008 by the European Molecular Biology Organization |
DOI: | 10.1038/sj.emboj.7601938 |
Published version: | http://dx.doi.org/10.1038/sj.emboj.7601938 |
Appears in Collections: | Aurora harvest 6 Molecular and Biomedical Science publications |
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