Insulin Receptor Domain Structure

The insulin receptor (IR) is a glycosylated, disulfide-linked homodimer, with each monomer being made up of an a-chain that is entirely extracellular and a P-chain that spans the cell membrane once. The a-chain contains the insulin-binding determinants of the receptor, while the intracellular portion of the P-chain includes a protein-tyrosine kinase domain and domains involved in binding signal transduction proteins. The aP monomer of the IR is encoded by a gene with 22 exons; alternative splicing of the IR pre-mRNA

leads to the tissue-specific expression of two isoforms differing by the presence or absence of a 12-residue segment (exon 11) near the C terminus of the a-chain. The receptor is synthesized as a single chain with a 27-residue signal sequence and is glycosylated, oxidized to the disulfide form, and proteolytically processed to the two-chain form during transport to the cell surface. The mature a-chain of the human IR has 731 amino acid residues, while the P-chain has 620. Two receptors with close sequence and structural homology to the IR are the receptor for insulin-like growth factor 1 (IGF-1R) and the orphan receptor, the insulin-receptor-related receptor (IRR) (see references [1] to [3] for reviews).

Analysis of the sequence of the IR has shown that the molecule can be divided into a number of modules or domains [4]. The ectodomain has two large homologous domains of approximately 150 residues, L1 and L2, separated by a 150-residue cysteine-rich domain; in this respect, the IR is similar to the epidermal growth factor receptor (EGFR). C-terminal to these, the IR has three fibronectin type III domains (FnIII-1, -2, and -3) of approximately 100 to 130 residues each. One of these, FnIII-2, has an insertion of 125 residues that contains the a-P cleavage site, resulting in the N-terminal region of FnIII-2 and part of the insert domain (ID) being found at the C terminus of the a-chain, and the remaining portions of these two domains being located at the N terminus of the P-chain. The domain structure of the IR ectodomain is shown schematically in Fig. 1. The discussion in this section focuses largely on the structure of the ectodomain and its interaction with the ligand, insulin. The structure of the kinase domain is discussed in Chapter 53.

Figure 1 Domain structure of the IR. Heavy lines, chain-linking disulfide bonds; P' refers to that portion of the P-chain that is extracellular.

The IR ectodomain has been shown to have a single disulfide bond linking the a- and P-chains, joining residues 647 and 872 (exon 11 plus form), and at least two disulfides symmetrically linking the a-chains of the dimer, one at residue 524 and the second at one of residues 682, 683, and 685. The human IR has 18 predicted sites for N-linked gly-cosylation: 14 on the a-chain and 4 on the P-chain. Of the 18 predicted N-linked sites, 16 are occupied by carbohydrate and one is unoccupied; O-linked glycans have been shown to occur on only 4 threonine and 2 serine residues in the 22 residues at the N terminus of the P-chain.

Although no crystal structure of the IR is yet available, a structure for a fragment of the homologous receptor, IGF-1R, has been published [5]. The structure of this fragment (Fig. 2), an expressed recombinant protein encompassing the L1-Cys-rich-L2 domains of the IGF-1R, should give a strong indication of the structure of the corresponding fragment of the IR.

Diabetes 2

Diabetes 2

Diabetes is a disease that affects the way your body uses food. Normally, your body converts sugars, starches and other foods into a form of sugar called glucose. Your body uses glucose for fuel. The cells receive the glucose through the bloodstream. They then use insulin a hormone made by the pancreas to absorb the glucose, convert it into energy, and either use it or store it for later use. Learn more...

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