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Structure and functional analysis of the IGF‐II/IGF2R interaction
Author(s) -
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
Publication year - 2008
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.1038/sj.emboj.7601938
Subject(s) - biology , insulin like growth factor 2 receptor , microbiology and biotechnology , receptor , plasma protein binding , binding site , growth factor , extracellular , biochemistry , insulin like growth factor 1 receptor
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.