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Review
. 2022 Feb;22(2):85-94.
doi: 10.1007/s11892-022-01447-2. Epub 2022 Feb 4.

Diabetes-Associated Mutations in Proinsulin Provide a "Molecular Rheostat" of Nascent Foldability

Balamurugan Dhayalan  1 , Michael A Weiss  2   3   4
Affiliations
Review

Diabetes-Associated Mutations in Proinsulin Provide a "Molecular Rheostat" of Nascent Foldability

Balamurugan Dhayalan et al. Curr Diab Rep. 2022 Feb.

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.

Keywords: Folding efficiency; Insulin; Insulin biosynthesis; Monogenic diabetes; Protein folding.

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