Crystal structure of the first three domains of the type-1 insulin-like growth factor receptor

Abstract

The type-1 insulin-like growth-factor receptor (IGF-1R) and insulin receptor (IR) are closely related members of the tyrosine-kinase receptor superfamily. IR is essential for glucose homeostasis, whereas IGF-1R is involved in both normal growth and development and malignant transformation. Homologues of these receptors are found in animals as simple as cnidarians. The epidermal growth-factor receptor (EGFR) family is closely related to the IR family and has significant sequence identity to the extracellular portion we describe here. We now present the structure of the first three domains of IGF-IR (L1-Cys-rich-L2) determined to 2.6 A resolution. The L domains each consist of a single-stranded right-handed beta-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. The three domains surround a central space of sufficient size to accommodate a ligand molecule. Although the fragment (residues 1-462) does not bind ligand, many of the determinants responsible for hormone binding and ligand specificity map to this central site. This structure therefore shows how the IR subfamily might interact with their ligands.

HER2/Neu: mechanisms of dimerization/oligomerization

“…Studies with the deletion mutants suggest that the extracellular domains of erbB receptor that small structural components in a subdomain may function not only to mediate dimerization in response to ligand, but also to prevent surreptitious dimerization. Recently we have modeled the three dimensional structure of the erbB-2 extracellular domain using the HER2/Neu: mechanisms of dimerization/oligomerization PJ Brennan et al insulin-like growth factor-1 receptor (Garrett et al, 1998) as a template and found that the fourth domain may be critical for dimer formation. Based on this model, we have developed a small peptide with cystineknot topology which shows varying degree of a nity to di erent members of erbB receptors.…”

Functionally significant insulin-like growth factor I receptor mutations in centenarians

“…Moreover, close to Arg-407 is the DAF-2 mutation Ala-580-Thr (e1365) that leads to dauer formation at 25°C (31). Finally, it is tempting to speculate that the altered IGF signaling induced by the synonymous mutation, 1545GϾA (Thr-470-Thr), may be caused by the reduction of IGFIR levels, as demonstrated in the lymphocytes from the (24). Colorcoded residues are those when mutated reduce the binding affinity of IGFI for IGFIR by 2-to 10-fold (pale pink) or Ͼ20-fold (red) (23) or a compound heterozygote missense mutations (hot pink) from a patient with intrauterine and postnatal growth retardation (22).…”

“…Our modeling using the crystal structure of the L1-CR1-L2 fragments of the IGFIR structure (24) shows that Ala-37 is positioned on a loop in the first L1 domain near residues that, when mutated, reduce the binding affinity of IGFI for IGFIR by 2-to 10-fold (Fig. 3, residues in pale pink) or Ͼ20-fold (Fig.…”

Decorin, a Novel Player in the Insulin-like Growth Factor System

“…On the decorin core protein, a binding region comprising leucine-rich repeat 7 was identified (15). The IGF-I binding domain of the IGF-IR is structurally related to the binding domain of the EGF receptor (27), but in the homologous region of the L2 domain of the IGF-IR (Phe-371-Leu-377) compared with the L2 domain of the EGF receptor (His-394-Ile-402) the acidic amino acids (Glu-397, Glu-400; EGF receptor) are substituted by basic amino acids (Lys-373, Arg-376; IGF-IR), indicating that this stretch of amino acids in the IGF-IR may have different properties. In addition, the site of interaction for the IGF-RI on the decorin core protein is very likely to be different.…”