Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P11021 (BiP)
 2,049 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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.
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PMID:Hsp70 family molecular chaperones and mutant insulin receptor: differential binding specificities of BiP and Hsp70/Hsc70 determines accumulation or degradation of insulin receptor. 856 76

Glucose deprivation leads to the synthesis of an aberrantly glycosylated ('alternative') and inefficiently processed form of the insulin proreceptor in 3T3-L1 adipocytes. To further explore the effect of aberrant (rather than absent) N-linked glycosylation of the insulin receptor, we examined the relationship of processing to function. Our studies show that the alternative form of the proreceptor does not oligomerize nor does it acquire the ability to undergo insulin-sensitive autophosphorylation. This along with an interaction with the glucose-regulated stress protein GRP78/BiP implies inappropriate folding/dimerization and retention in the ER. Glucose refeeding causes the post-translational modification of the alternative form of the proreceptor to a novel 'intermediate' form which is independent of new protein synthesis. As little as 100 microM glucose (or mannose) can induce this modification. In vitro digestion of the alternative and intermediate proreceptors with SPC1/furin shows that both the alpha- and beta-subunit domains are glycosylated, albeit aberrantly. This implies that the aberrantly glycosylated proreceptor could serve as a substrate for SPC1 in a physiological setting if the receptor was able to interact with the enzyme in the appropriate compartment (i.e., the trans-Golgi network). Based on inhibitor studies, however, both the alternative and intermediate forms of the proreceptor appear to be primarily targeted to the proteasome for degradation.
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PMID:Alternative glycosylation of the insulin receptor prevents oligomerization and acquisition of insulin-dependent tyrosine kinase activity. 1111 40