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Structure and function of the insulin receptor

Jonathan Whittaker, MD, MRCP
Section Editor
Irl B Hirsch, MD
Deputy Editor
Jean E Mulder, MD


Insulin initiates its cellular responses by binding to its cellular receptor, a transmembrane, multi-subunit glycoprotein that contains insulin-stimulated tyrosine kinase activity [1]. The cellular content of insulin receptors is variable, with the highest level of expression in cells that are most responsive to insulin for glucose, lipid, and protein metabolism, especially adipose, skeletal muscle, and liver. Initially identified over 25 years ago [2], the insulin receptor cDNA was cloned in 1985 [3,4]. Crystal structures of its protein tyrosine and of its extracellular domains were determined in 1994 [5] and 2006 [6], respectively. Since insulin has profound importance in metabolic control, studies of its receptor protein have been the subject of intense investigation [7].


Receptor gene and mRNA — The insulin receptor gene maps to human chromosome 19 and spans more than 150 kilobases (kb) [8]. The 22 exons of the receptor gene are transcribed into several mRNA species ranging from 4.2 to 9.5 kb in length due to variation in their 3'-untranslated regions [9]. Exon 11, which encodes a 12 amino acid segment localized to the C-terminus of the α-subunit, is subject to tissue-specific alternative splicing in a pattern conserved between humans and lower mammals (figure 1) [10-12].

The abundance of receptor mRNA and protein are up-regulated by differentiation of adipocyte and muscle precursor cells as they acquire an insulin-sensitive phenotype [13]. In some cells, exposure to insulin reduces receptor mRNA abundance, which may play a role in regulation of receptor number in vivo [14,15]. In rare cases of severe insulin resistance due to mutations in the receptor gene, extreme reduction in receptor abundance has been shown [16]. However, altered receptor abundance is not believed to play a major role in common forms of insulin resistance in obesity or type 2 diabetes.

The primary translation product of the insulin receptor mRNA is a linear α-ß sequence of the insulin receptor precursor (proreceptor). The signal sequence of 27 hydrophobic amino acids at the N-terminus of the α-subunit allows the receptor to enter the endoplasmic reticulum, during which process the signal peptide is cleaved. The proreceptor is further proteolytically-processed by furin in the Golgi apparatus into distinct α and ß-subunits at a cleavage site consisting of four basic amino acids (Arg-Lys-Arg-Arg) [17-20], apparently after disulfide linkage of two proreceptor molecules [21].

Receptor structure — The receptor is composed of two extracellular α-subunits that are each linked to a ß-subunit and to each other by disulfide bonds (figure 2). Reduction of the bonds that link the α-subunits produces an α-ß monomer that binds insulin with reduced affinity [22,23] and that is devoid of insulin stimulated tyrosine kinase activity [24,25]. Reconstitution of such hetero-dimers into hetero-tetramers restores both high affinity insulin binding and insulin stimulated kinase activity [24,25].


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