LAUSR

Insulin Receptor (IR) mediated signaling is crucial in controlling glucose homeostasis, regulating lipid, protein and carbohydrate metabolism, and modulating brain neurotransmitter levels [1, 2]. Aberrations in Insulin signaling have been associated with a variety of disease states, including diabetes, cancer and Alzheimer’s [1, 3, 4]. IR is composed of two heterodimers ( and  chains), each containing an extracellular portion (ectodomain), a single transmembrane helix (TM), and a cytoplasmic tyrosine kinase domain (TK) (Figure 1). One single disulfide bond links the  and  chains in the monomer, while the dimer is stabilized by two interchain disulfide bonds (Figure 1). Insulin is thought to bind to two distinct sites (per monomer), in a complex process that exhibits negative cooperativity [5]. Insulin binding site 1 was mapped by alanine scanning to portion of the L1 domain (Asp12-Asn15, Leu37, Phe39, Phe64 and Arg65) and to the CT helix (Gln692-Pro718) located at the C-terminal end of the ID domain. Site 2 was mapped to loop regions near the junction between the FNIII-1 and FNIII-2 domains [5 and references therein].