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

EMBO J. 2008 Jan 9;27(1):265-76. doi: 10.1038/sj.emboj.7601938. Epub 2007 Nov 29.


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.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't
  • Validation Study

MeSH terms

  • Animals
  • CHO Cells
  • Cell Line
  • Cricetinae
  • Cricetulus
  • Crystallography, X-Ray
  • Humans
  • Insulin-Like Growth Factor II / chemistry*
  • Insulin-Like Growth Factor II / genetics
  • Insulin-Like Growth Factor II / physiology*
  • Mutagenesis
  • Protein Binding / physiology
  • Protein Structure, Tertiary
  • Receptor, IGF Type 2 / chemistry*
  • Receptor, IGF Type 2 / genetics
  • Receptor, IGF Type 2 / physiology*
  • Structure-Activity Relationship


  • Receptor, IGF Type 2
  • Insulin-Like Growth Factor II

Associated data

  • PDB/2V5N
  • PDB/2V5O
  • PDB/2V5P