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 c haperones, BiP and Hsp70/Hsc70, to wild-type or mutant insulin recepto rs. BiP bound to proreceptor of wild-type insulin receptor, but not to mature receptor. A mutant insulin receptor, which lacked 47 amino aci d residues (Delta Ex13 IR) corresponding to exon 13 of insulin recepto r gene, accumulated in the endoplasmic reticulum as uncleaved prorecep tor with immature oligosaccharide chains. This deletion mutant bound t o BiP more tightly than wild type. Introduction of two types of mutati ons, Asp(1179) or Leu(1193), into Delta Ex13 IR led to accelerated deg radation, and these double mutants bound weakly to BiP. In contrast, S er(735) insulin receptor was normally transported to the plasma membra ne and normally bound to BiP. Furthermore, Asp(1179), Leu(1193) insuli n receptors and Delta Ex13 IR combination mutant with either Asp(1179) or Leu(1193) bound more tightly to Hsp70/Hsc70 compared with wild-typ e, Ser(735), and Delta Ex13 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 posttrans lational processing that map lead to the accumulation in the endoplasm ic reticulum or the degradation of insulin receptors. (C) 1996 Academi c Press, Inc.