Cys 786 and Cys 776 in the posttranslational processing of the insulin andIGF-I receptors

The extracellular regions of insulin and IGF I receptors (IR and IGF-IR) co ntain fibronectin type III repeats with cysteine residues potentially invol ved in S=S bond. In this report we show that Cys 786 in the IR and the corr esponding Cys 776 in the IGF-IR regulate proreceptor dimerization with high specificity. Both C786S insulin and C776S IGF-I proreceptors reach the mon omeric 210-kDa step, but do not proceed further. Mature IRC786S and IGF-IRC 776S expression on plasmamembrane is abolished. No retention of C786S IR pr ecursor was detected in the endoplasmic reticulum, which is degraded by a n onlysosomal mechanism. The rearrangement of the remaining cysteines in the insulin receptor beta subunit ectodomain does not rescue dimerization of C7 86S insulin proreceptor. As observed in other transmembrane receptors, iuxt amembrane cysteines, specifically Cys 786 in the IR and Cys 776 in the IGF- IR, are critical for correct processing of proreceptors. (C) 2001 Academic Press.