A comparative structural bioinformatics analysis of the insulin receptor family ectodomain based on phylogenetic information.
The insulin receptor (IR), the insulin-like growth factor 1 receptor (IGF1R) and the insulin receptor-related receptor (IRR) are covalently-linked homodimers made up of several structural domains. The molecular mechanism of ligand binding to the ectodomain of these receptors and the resulting activation of their tyrosine kinase domain is still not well understood. We have carried out an amino acid residue conservation analysis in order to reconstruct the phylogeny of the IR Family. We have confirmed the location of ligand binding site 1 of the IGF1R and IR. Importantly, we have also predicted the likely location of the insulin binding site 2 on the surface of the fibronectin type III domains of the IR. An evolutionary conserved surface on the second leucine-rich domain that may interact with the ligand could not be detected. We suggest a possible mechanical trigger of the activation of the IR that involves a slight 'twist' rotation of the last two fibronectin type III domains in order to face the likely location of insulin. Finally, a strong selective pressure was found amongst the IRR orthologous sequences, suggesting that this orphan receptor has a yet unknown physiological role which may be conserved from amphibians to mammals.
Rentería
Miguel E
ME
Western Australian Biomedical Research Institute and School of Biomedical Sciences, Curtin University of Technology, Perth, Western Austrailia, Australia.
Gandhi
Neha S
NS
Vinuesa
Pablo
P
Helmerhorst
Erik
E
Mancera
Ricardo L
RL
D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D019295:Computational Biology; D017124:Conserved Sequence; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010802:Phylogeny; D017434:Protein Structure, Tertiary; D017526:Receptor, IGF Type 1 / Q000737:chemistry / Q000235:genetics; D011972:Receptor, Insulin / Q000737:chemistry* / Q000235:genetics; D013329:Structure-Activity Relationship
D008024:Ligands; D017526:Receptor, IGF Type 1; D011972:Receptor, Insulin