Rentería Miguel E, Gandhi Neha S, Vinuesa Pablo, Helmerhorst Erik, Mancera Ricardo L
Western Australian Biomedical Research Institute and School of Biomedical Sciences, Curtin University of Technology, Perth, Western Austrailia, Australia.
PLoS One. 2008;3(11):e3667. doi: 10.1371/journal.pone.0003667. Epub 2008 Nov 7.
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.
胰岛素受体（IR）、胰岛素样生长因子1受体（IGF1R）和胰岛素受体相关受体（IRR）是由几个结构域组成的共价连接的同型二聚体。配体与这些受体胞外结构域结合以及由此导致其酪氨酸激酶结构域激活的分子机制仍未完全清楚。我们进行了氨基酸残基保守性分析，以重建IR家族的系统发育。我们确定了IGF1R和IR的配体结合位点1的位置。重要的是，我们还预测了胰岛素结合位点2在IR的III型纤连蛋白结构域表面的可能位置。未检测到富含亮氨酸的第二个结构域上可能与配体相互作用的进化保守表面。我们提出了一种可能的IR激活机械触发机制，该机制涉及最后两个III型纤连蛋白结构域的轻微“扭转”旋转，以便面对胰岛素的可能位置。最后，在IRR直系同源序列中发现了强烈的选择压力，表明这种孤儿受体具有尚未明确的生理作用，该作用可能从两栖动物到哺乳动物都保守存在。
