Substitution of glutamine for arginine 1131. A newly identified mutation in the catalytic loop of the tyrosine kinase domain of the human insulin receptor.

摘要: We studied a patient with severe insulin resistance and remarkable decrease in the vivo autophosphorylation of receptor. Using polymerase chain reaction-single strand conformation polymorphism method direct sequencing, we identified heterozygous mutation substituting Gln for Arg1131 putative "catalytic loop" tyrosine kinase domain receptor gene. The Gln1131 mutant was expressed by transfection Chinese hamster ovary cells compared expressing wild-type Both receptors were on cell surface displayed similar insulin-binding affinity. impaired activity inhibited ability to phosphorylate endogenous substrate substrate-I. In addition, exhibited diminished tyrosine-phosphorylated phosphatidylinositol 3-kinase myelin basic protein activities cells. It also demonstrated defective mediation signal stimulating 2-deoxy-D-glucose transport thymidine incorporation, endocytosis, insulin-induced down-regulation. Unlike previously described catalytic loop that substituted Glu Ala1135, retained proteolytic cleavage proreceptor into separate subunits. Our results demonstrate naturally occurring (R1131Q) impairment function our patient. indicate is important receptor-mediated action suggest amino acids constituting kinases may possess different modes order retain function.