RILM: a web-based resource to aid comparative and functional analysis of the insulin and IGF-1 receptor family

Abstract

The metazoan receptors for insulin (INSR), insulin-like growth factor 1 (IGF1R), and other insulin-like molecules are transmembrane tyrosine kinases involved in the regulation of cell size, cell proliferation, development, signaling of nutritional and environmental conditions, and aging. Historically, mutations in the human insulin receptor have been studied because such changes often lead to severe insulin resistance. More recently, amino acid sequence alterations in the insulin receptor-like receptors of Drosophila melanogaster and Caenorhabditis elegans, as well as in the mouse insulin receptor have been the focus of attention. These modifications can have profound effects on growth, body size, metabolism, and aging. To integrate the many findings on insulin/IGF1 receptor structure and function across species we have created "Receptors for Insulin and Insulin-like Molecules" (RILM), a curated computer-based resource that displays residue-by-residue information on sequence homology, three-dimensional structure, structure/function annotation, and documented mutations. The resource includes data obtained from sequence and structure analysis tools, primary database resources, and published reports. The information is integrated via a structure-based multiple sequence alignment of diverse members of the family. RILM was designed to provide easy access to multiple data types that could prove useful in the analysis of the effect of mutations on protein structure and ligand binding within this receptor family. RILM is available at www.biochem.ucl.ac.uk/RILM.

Figure 1

Schematic representation of the structure of the RILM web resource, indicating the seamlessly connected (thick double-headed arrows) core data elements in the centre (grey), modes of entry to the multiple sequence alignment and derived structural and functional data at left, and background textual information at right.

Figure 2

Screen snapshot of the cross-phyla multiple sequence alignment at the core of RILM. The example shown is for the L1 domain. In the on-line web resource each residue is given a background color according to conventional categorisation of the physicochemical properties of the side chain. The cursor bar at bottom allows one to easily move along the sequence within a given domain. Jumping between domains is enabled by navigational tools at the top (here the right arrow provides a link to the CRR domain that follows L1). The snapshot illustrates the amino acid residue identification at the current cursor position (here Cys26 of INSR).

Figure 3

Screen snapshot of the derived structural and functional data for a specific residue from the RILM web resource. The example shown is for Gly547 of C. elegans daf-2 which is described in more detail in the main text. The snapshot illustrates the navigational features of RILM at top. Browsing of the sequence alignment is facilitated by clicking on the ‘forward’, ‘rewind’, ‘fast-forward’ and ‘fast-rewind’ buttons, or by jumping between component domains. The Jmol applet at the bottom of the figure illustrates how the user is able to call up a view of the position of the selected residue in the most appropriate experimental 3D structure.