Abstract
Comparative sequence analyses have revealed that many proteins are composed of a number of different, sometimes repeated, structural units. In the case of the insulin receptor subfamily, 11 distinct regions have been identified in each monomer. The N-terminal half of the ectodomain contains two homologous domains (L1 and L2), separated by a cys-rich region containing 24–26 cysteines. The Cterminal half of the ectodomain consists of three fibronectin type III domains, the second of which contains a large insert domain. Experimental structural information has been obtained from crystals of a fragment (residues 1–462) comprising the L1-cysteine-rich-L2 region of the IGF-IR ectodomain. The molecule adopts an extended structure with a central space, bounded by all three domains, of sufficient size to accommodate ligand. Two regions of the receptor which are involved in hormone binding, map to this central site. Each L domains adopts a compact shape consisting of a single stranded right-handed β-helix. The cys-rich region is composed of eight disulfide-bonded modules, seven of which form a rod-shaped domain with modules associated in a novel manner. While they resemble the modules found in the TNF receptor and laminin repeats, this novel arrangement suggests that EGF repeats found in many proteins are composed of two smaller modules containing two or one disulfide bond. Single-molecule electron microscope imaging has revealed that the IR ectodomain resembles a compact U-shaped prism, where the Ll-cys rich-L2 domains occupy the membrane distal region and the fibronectin type III and insert domains are located in the membrane-proximal third.
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Ward, C.W., Garrett, T.P.J., McKern, N.M., Sparrow, L.G., Frenkel, M.J. (2002). Structural Relationships between Members of the Insulin Receptor Family. In: Dieken, M.L., Federwisch, M., De Meyts, P. (eds) Insulin & Related Proteins - Structure to Function and Pharmacology. Springer, Dordrecht. https://doi.org/10.1007/0-306-47582-0_12
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DOI: https://doi.org/10.1007/0-306-47582-0_12
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