Structure of the insulin receptor ectodomain reveals a folded-over conformation.
The insulin receptor is a phylogenetically ancient tyrosine kinase receptor found in organisms as primitive as cnidarians and insects. In higher organisms it is essential for glucose homeostasis, whereas the closely related insulin-like growth factor receptor (IGF-1R) is involved in normal growth and development. The insulin receptor is expressed in two isoforms, IR-A and IR-B; the former also functions as a high-affinity receptor for IGF-II and is implicated, along with IGF-1R, in malignant transformation. Here we present the crystal structure at 3.8 A resolution of the IR-A ectodomain dimer, complexed with four Fabs from the monoclonal antibodies 83-7 and 83-14 (ref. 4), grown in the presence of a fragment of an insulin mimetic peptide. The structure reveals the domain arrangement in the disulphide-linked ectodomain dimer, showing that the insulin receptor adopts a folded-over conformation that places the ligand-binding regions in juxtaposition. This arrangement is very different from previous models. It shows that the two L1 domains are on opposite sides of the dimer, too far apart to allow insulin to bind both L1 domains simultaneously as previously proposed. Instead, the structure implicates the carboxy-terminal surface of the first fibronectin type III domain as the second binding site involved in high-affinity binding.
McKern
Neil M
NM
CSIRO Molecular & Health Technologies, 343 Royal Parade, Parkville, Victoria 3052, Australia.
Lawrence
Michael C
MC
Streltsov
Victor A
VA
Lou
Mei-Zhen
MZ
Adams
Timothy E
TE
Lovrecz
George O
GO
Elleman
Thomas C
TC
Richards
Kim M
KM
Bentley
John D
JD
Pilling
Patricia A
PA
Hoyne
Peter A
PA
Cartledge
Kellie A
KA
Pham
Tam M
TM
Lewis
Jennifer L
JL
Sankovich
Sonia E
SE
Stoichevska
Violet
V
Da Silva
Elizabeth
E
Robinson
Christine P
CP
Frenkel
Maurice J
MJ
Sparrow
Lindsay G
LG
Fernley
Ross T
RT
Epa
V Chandana
VC
Ward
Colin W
CW
D018360:Crystallography, X-Ray; D019281:Dimerization; D007140:Immunoglobulin Fab Fragments / Q000276:immunology; D008854:Microscopy, Electron; D008958:Models, Molecular; D017510:Protein Folding; D020836:Protein Structure, Quaternary; D017434:Protein Structure, Tertiary; D011972:Receptor, Insulin / Q000737:chemistry* / Q000276:immunology / Q000378:metabolism* / Q000648:ultrastructure
D007140:Immunoglobulin Fab Fragments; D011972:Receptor, Insulin