ABSTRACT
Address correspondence to Dr. J.Bass at present address: Northwestern University Medical School and the Evanston Northwestern Research Institute, ITEC #6303, 1801 Maple Avenue, Evanston, IL 60693. Phone: (847) 467-5973 Email: jbass@northwestern.edu
SUMMARY
Central to the maintenance of blood glucose homeostasis is the interaction of insulin with membrane-spanning receptors present on the surface of most cells. Delivery of functional insulin receptors to the cell surface affects insulin sensitivity and impairment of this process can cause diabetes mellitus. Like other integral membrane proteins, the ratelimiting step in the intracellular transport of the insulin receptor involves protein folding, the process by which the linear amino acid sequence of the receptor gives rise to a precise three-dimensional structure. During the past decade, several families of novel proteins have been discovered which assist in the folding and assembly of all proteins in the cell. The task of these proteins, termed molecular chaperones, is to prevent the aggregation and misfolding of substrate proteins prior to the acquisition of a native structure. By modulating conformational maturation of diverse substrates, molecular chaperones introduce an additional level in the regulation of functional gene expression and exert broad biologic effects. In this review we summarize present information on the function and mechanisms of ER molecular chaperones in the folding of the lumenal domain of the insulin receptor. Interaction with molecular chaperones determines the fate of newly synthesized receptors: failure to dissociate from chaperones is a preliminary step in the degradation of certain malformed membrane proteins and is one component in the ER quality control system. The challenge remaining for future research includes the dissection of both the molecular basis of chaperone-receptor interactions and the elucidation of the mechanisms by which missense mutations in the receptor gene and acquired defects in receptor folding mark aberrant forms for destruction. Insight gained from this research will contribute to our understanding both of the major structural elements necessary for receptor function and the posttranslational control of receptor expression in health and disease.
