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 (delta Ex13 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 delta Ex13 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 delta Ex13 IR combination mutant with either Asp1179 or Leu1193 bound more tightly to Hsp70/Hsc70 compared with wild-type, Ser735, 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 posttranslational processing that may lead to the accumulation in the endoplasmic reticulum or the degradation of insulin receptors.
Sawa
T
T
First Department of Medicine, Toyama Medical and Pharmaceutical University, Japan.
Imamura
T
T
Haruta
T
T
Sasaoka
T
T
Ishiki
M
M
Takata
Y
Y
Takada
Y
Y
Morioka
H
H
Ishihara
H
H
Usui
I
I
Kobayashi
M
M
D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism*; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D000091342:Endoplasmic Reticulum Chaperone BiP; D050883:HSC70 Heat-Shock Proteins; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism*; D006360:Heat-Shock Proteins; D018832:Molecular Chaperones / Q000378:metabolism*; D009154:Mutation; D011233:Precipitin Tests; D011972:Receptor, Insulin / Q000235:genetics / Q000378:metabolism*; D011994:Recombinant Proteins; D013329:Structure-Activity Relationship
D002352:Carrier Proteins; D000091342:Endoplasmic Reticulum Chaperone BiP; D050883:HSC70 Heat-Shock Proteins; D018840:HSP70 Heat-Shock Proteins; D006360:Heat-Shock Proteins; D018832:Molecular Chaperones; D011994:Recombinant Proteins; D011972:Receptor, Insulin