Review

The three dimensional structure of the type I insulin-like growth factor receptor

C W Ward¹, T P J Garrett², N M McKern¹, M Lou², L J Cosgrove³, L G Sparrow¹, M J Frenkel¹, P A Hoyne¹, T C Elleman¹, T E Adams¹, G O Lovrecz¹, L J Lawrence² and P A Tulloch²

¹ CSIRO Health Sciences and Nutrition, Parkville Laboratory, 343 Royal Parade, Parkville, Victoria, 3052, Australia
² Biomolecular Research Institute, 343 Royal Parade, Parkville, Victoria, 3052, Australia
³ CSIRO Health Sciences and Nutrition, Kintore Avenue, Adelaide, South Australia, 5000, Australia

Correspondence to:
Dr Ward Colin.Ward{at}hsn.csiro.au

Ever since the discovery of insulin and its role in the regulation of glucose metabolism, there has been great interest in the molecule itself, the insulin-like growth factors (IGFs), and their receptors (IR and IGF-R). These receptors form a subfamily of tyrosine kinase receptors which are large, transmembrane proteins consisting of several structural domains. Their ectodomains have a similar arrangement of two homologous domains (L1 and L2) separated by a Cys rich region. The C-terminal half of their ectodomains consists of three fibronectin type 3 repeats, and an insert domain that contains the –ß cleavage site. This review summarises the key developments in the understanding of the structure of this family of receptors and their relation to other multidomain proteins. Data presented will include multiple sequence analyses, single molecule electron microscope images of the IGF-1R, insulin receptor (IR), and IR–Fab complexes, and the three dimensional structure of the first three domains of the IGF-1R determined to 2.6 Å resolution by x ray crystallography. The L domains each adopt a compact shape consisting of a single stranded, right handed ß-helix. The Cys rich region is composed of eight disulphide bonded modules, seven of which form a rod shaped domain with modules associated in an unusual manner.

Key Words: insulin-like growth factor • insulin • receptors • three dimensional structure • electron microscopy

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