Structure and functional analysis of the IGF-II/IGF2R interaction.
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.
Cancer Research UK Receptor Structure Research Group, Division of Structural Biology, Wellcome Trust Centre for Human Genetics, University of Oxford, Headington, Oxford, UK.
James
J
Brown
Carlie
C
Delaine
Oliver J
OJ
Zaccheo
Christian
C
Siebold
Robert J
RJ
Gilbert
Gijs
G
van Boxel
Adam
A
Denley
John C
JC
Wallace
A Bassim
AB
Hassan
Briony E
BE
Forbes
E Yvonne
EY
Jones
D000818:Animals; D016466:CHO Cells; D002460:Cell Line; D006224:Cricetinae; D003412:Cricetulus; D018360:Crystallography, X-Ray; D006801:Humans; D007335:Insulin-Like Growth Factor II / Q000737:chemistry* / Q000235:genetics / Q000502:physiology*; D016296:Mutagenesis; D011485:Protein Binding / Q000502:physiology; D017434:Protein Structure, Tertiary; D017527:Receptor, IGF Type 2 / Q000737:chemistry* / Q000235:genetics / Q000502:physiology*; D013329:Structure-Activity Relationship
D017527:Receptor, IGF Type 2; D007335:Insulin-Like Growth Factor II