Proinsulin and the genetics of diabetes mellitus.
Insulin plays a central role in the regulation of vertebrate metabolism. The hormone, the post-translational product of a single-chain precursor, is a globular protein containing two chains, A (21 residues) and B (30 residues). Recent advances in human genetics have identified dominant mutations in the insulin gene causing permanent neonatal-onset DM(2) (1-4). The mutations are predicted to block folding of the precursor in the ER of pancreatic beta-cells. Although expression of the wild-type allele would in other circumstances be sufficient to maintain homeostasis, studies of a corresponding mouse model (5-7) suggest that the misfolded variant perturbs wild-type biosynthesis (8, 9). Impaired beta-cell secretion is associated with ER stress, distorted organelle architecture, and cell death (10). These findings have renewed interest in insulin biosynthesis (11-13) and the structural basis of disulfide pairing (14-19). Protein evolution is constrained not only by structure and function but also by susceptibility to toxic misfolding.
Weiss
Michael A
MA
Department of Biochemistry, Case Western Reserve University, Cleveland, Ohio 44106, USA. michael.weiss@case.edu
D000818:Animals; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007328:Insulin / Q000235:genetics / Q000378:metabolism; D008954:Models, Biological; D009154:Mutation; D011384:Proinsulin / Q000096:biosynthesis / Q000737:chemistry* / Q000235:genetics; D017510:Protein Folding; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary
D007328:Insulin; D011384:Proinsulin