Balamurugan Dhayalan1, Michael A Weiss2,3,4. 1. Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN, 46202, USA. 2. Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN, 46202, USA. weissma@iu.edu. 3. Department of Chemistry, Indiana University, Bloomington, IN, 47405, USA. weissma@iu.edu. 4. Weldon School of Biomedical Engineering, Purdue University, West Lafayette, IN, 47907, USA. weissma@iu.edu.
Abstract
PURPOSE OF REVIEW: Diabetes mellitus (DM) due to toxic misfolding of proinsulin variants provides a monogenic model of endoplasmic reticulum (ER) stress. The mutant proinsulin syndrome (also designated MIDY; Mutant INS-gene-induced Diabetes of Youth or Maturity-onset diabetes of the young 10 (MODY10)) ordinarily presents as permanent neonatal-onset DM, but specific amino-acid substitutions may also present later in childhood or adolescence. This review highlights structural mechanisms of proinsulin folding as inferred from phenotype-genotype relationships. RECENT FINDINGS: MIDY mutations most commonly add or remove a cysteine, leading to a variant polypeptide containing an odd number of thiol groups. Such variants are associated with aberrant intermolecular disulfide pairing, ER stress, and neonatal β-cell dysfunction. Non-cysteine-related (NCR) mutations (occurring in both the B and A domains of proinsulin) define distinct determinants of foldability and vary in severity. The range of ages of onset, therefore, reflects a "molecular rheostat" connecting protein biophysics to quality-control ER checkpoints. Because in most mammalian cell lines even wild-type proinsulin exhibits limited folding efficiency, molecular barriers to folding uncovered by NCR MIDY mutations may pertain to β-cell dysfunction in non-syndromic type 2 DM due to INS-gene overexpression in the face of peripheral insulin resistance. Recent studies of MIDY mutations and related NCR variants, combining molecular and cell-based approaches, suggest that proinsulin has evolved at the edge of non-foldability. Chemical protein synthesis promises to enable comparative studies of "non-foldable" proinsulin variants to define key steps in wild-type biosynthesis. Such studies may create opportunities for novel therapeutic approaches to non-syndromic type 2 DM.
PURPOSE OF REVIEW: Diabetes mellitus (DM) due to toxic misfolding of proinsulin variants provides a monogenic model of endoplasmic reticulum (ER) stress. The mutant proinsulin syndrome (also designated MIDY; Mutant INS-gene-induced Diabetes of Youth or Maturity-onset diabetes of the young 10 (MODY10)) ordinarily presents as permanent neonatal-onset DM, but specific amino-acid substitutions may also present later in childhood or adolescence. This review highlights structural mechanisms of proinsulin folding as inferred from phenotype-genotype relationships. RECENT FINDINGS: MIDY mutations most commonly add or remove a cysteine, leading to a variant polypeptide containing an odd number of thiol groups. Such variants are associated with aberrant intermolecular disulfide pairing, ER stress, and neonatal β-cell dysfunction. Non-cysteine-related (NCR) mutations (occurring in both the B and A domains of proinsulin) define distinct determinants of foldability and vary in severity. The range of ages of onset, therefore, reflects a "molecular rheostat" connecting protein biophysics to quality-control ER checkpoints. Because in most mammalian cell lines even wild-type proinsulin exhibits limited folding efficiency, molecular barriers to folding uncovered by NCR MIDY mutations may pertain to β-cell dysfunction in non-syndromic type 2 DM due to INS-gene overexpression in the face of peripheral insulin resistance. Recent studies of MIDY mutations and related NCR variants, combining molecular and cell-based approaches, suggest that proinsulin has evolved at the edge of non-foldability. Chemical protein synthesis promises to enable comparative studies of "non-foldable" proinsulin variants to define key steps in wild-type biosynthesis. Such studies may create opportunities for novel therapeutic approaches to non-syndromic type 2 DM.
Authors: Denis Canet; Alexander M Last; Paula Tito; Margaret Sunde; Andrew Spencer; David B Archer; Christina Redfield; Carol V Robinson; Christopher M Dobson Journal: Nat Struct Biol Date: 2002-04
Authors: Yoshiki Sekijima; R Luke Wiseman; Jeanne Matteson; Per Hammarström; Sean R Miller; Anu R Sawkar; William E Balch; Jeffery W Kelly Journal: Cell Date: 2005-04-08 Impact factor: 41.582