title: Structural insights into the interaction of insulin-like growth factor 2 with IGF2R domain 11.
abstract: The insulin-like growth factor II/mannose-6-phosphate receptor (IGF2R) mediates trafficking of mannose-6-phosphate (M6P)-containing proteins and the mitogenic hormone IGF2. IGF2R also plays an important role as a tumor suppressor, as mutation is frequently associated with human carcinogenesis. IGF2 binds to domain 11, one of 15 extracellular domains on IGF2R. The crystal structure of domain 11 and the solution structure of IGF2 have been reported, but, to date, there has been limited success when using crystallography to study the interaction of IGFs with their binding partners. As an approach to investigate the interaction between IGF2 and IGF2R, we have used heteronuclear NMR in combination with existing mutagenesis data to derive models of the domain 11-IGF2 complex by using the program HADDOCK. The models reveal that the molecular interaction is driven by critical hydrophobic residues on IGF2 and IGF2R, while a ring of flexible, charged residues on IGF2R may modulate binding.
authors.affiliation: Department of Organic and Biological Chemistry, School of Chemistry, Cantock's Close, University of Bristol, Bristol, United Kingdom.
authors.forename: Christopher
authors.initials: C
authors.lastname: Williams
authors.forename: Dellel
authors.initials: D
authors.lastname: Rezgui
authors.forename: Stuart N
authors.initials: SN
authors.lastname: Prince
authors.forename: Oliver J
authors.initials: OJ
authors.lastname: Zaccheo
authors.forename: Emily J
authors.initials: EJ
authors.lastname: Foulstone
authors.forename: Briony E
authors.initials: BE
authors.lastname: Forbes
authors.forename: Raymond S
authors.initials: RS
authors.lastname: Norton
authors.forename: John
authors.initials: J
authors.lastname: Crosby
authors.forename: A Bassim
authors.initials: AB
authors.lastname: Hassan
authors.forename: Matthew P
authors.initials: MP
authors.lastname: Crump
mesh_terms: D000595:Amino Acid Sequence; D001483:Base Sequence; D002851:Chromatography, High Pressure Liquid; D017931:DNA Primers; D006801:Humans; D007335:Insulin-Like Growth Factor II; D008969:Molecular Sequence Data; D016296:Mutagenesis; D019906:Nuclear Magnetic Resonance, Biomolecular; D016133:Polymerase Chain Reaction; D011485:Protein Binding; D011487:Protein Conformation; D011506:Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D017527:Receptor, IGF Type 2 / Q000378:metabolism*; D017386:Sequence Homology, Amino Acid; D020349:Surface Plasmon Resonance
chemical_list: D017931:DNA Primers; C035170:IGF2 protein, human; D011506:Proteins; D017527:Receptor, IGF Type 2; D007335:Insulin-Like Growth Factor II