Insulin Receptor

Using x-ray crystallography as our primary experimental technique, we are attempting to understand the molecular basis for insulin receptor activation and for recruitment of downstream signaling proteins to the activated (phosphorylated) insulin receptor. Several cytoplasmic adapter proteins bind to the activated insulin receptor, including insulin receptor substrate (IRS) proteins and APS, which are positive factors in insulin signaling pathways culminating in glucose uptake. The insulin receptor is downregulated by the adapter proteins Grb14 and Grb10 as well as the tyrosine phosphatase PTP1B. We are determining crystal structures of complexes between these proteins and the insulin receptor kinase domain to elucidate the modes of interaction and the determinants of specificity.

 

Model of the interaction between Grb14 and the activated insulin receptor. [Depetris et al., Nat. Struct. Mol. Biol. 16, 833-839 (2009)]
 
The KRLB region of IRS2 bound to tri-phosphorylated IRK. The N-terminal kinase lobe is colored dark gray, the C-terminal lobe is colored light gray, and the KRLB region (residues 620-634) is shown in stick representation. Atoms of the activation loop and catalytic loop of IRK are colored green and orange, respectively. [Wu et al., Nat. Struct. Mol. Biol. 15, 251-258 (2008)]