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

Journal article

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.

Authors: Brown, J; Delaine, C; Zaccheo, O; Siebold, C; Gilbert, R

• Publication status: Published
• Journal: EMBO journal
• Volume: 27
• Issue: 1
• Pages: 265-276
• Publication date: 2008-01-01
• DOI: 10.1038/sj.emboj.7601938
• EISSN: 1460-2075
• ISSN: 0261-4189
• Language: English
• Keywords: Protein Binding; Humans; Crystallography, X-Ray; CHO Cells; Structure-Activity Relationship; Protein Structure, Tertiary; Insulin-Like Growth Factor II; Receptor, IGF Type 2; Cell Line; Cricetinae; Animals; Mutagenesis; Cricetulus