Hsp70 family molecular chaperones and mutant insulin receptor: Differential binding specificities of BiP and Hsp70/Hsc70 determines accumulation or degradation of insulin receptor

We have examined the binding specificities of Hsp70 family molecular chaperones, BiP and Hsp70/Hsc70, to wild-type or mutant insulin receptors. BiP bound to proreceptor of wild-type insulin receptor. but not to mature receptor. A mutant insulin receptor, which lacked 47 amino acid residues (ΔEx13 IR) corresponding to exon 13 of insulin receptor gene, accumulated in the endoplasmic reticulum as uncleaved proreceptor with immature oligosaccharide chains. This deletion mutant bound to BiP more tightly than wild type. Introduction of two types of mutations, Asp¹¹⁷⁹ or Leu¹¹⁹³, into ΔEx13 IR led to accelerated degradation, and these double mutants bound weakly to BiP. In contrast, Ser⁷³⁵ insulin receptor was normally transported to the plasma membrane and normally bound to BiP. Furthermore, Asp¹¹⁷⁹, Leu¹¹⁹³ insulin receptors and ΔEx13 IR combination mutant with either Asp¹¹⁷⁹ Or Leu¹¹⁹³ bound more tightly to Hsp70/Hsc70 compared with wild-type, Ser⁷³⁵, and ΔEx13 IR. These results suggest that the binding specificity of mutant insulin receptors to two molecular chaperones, i.e., BiP and Hsp70/Hsc70, plays an important role for their posttranslational processing that may lead to the accumulation in the endoplasmic reticulum or the degradation of insulin receptors.