Synthetic studies of the mutant proinsulin syndrome demonstrate correlation between folding efficiency and age of diabetes onset.

ABSTRACT:

Purpose

Heterozygous mutations in the insulin gene can give rise to a monogenic diabetes syndrome due to toxic misfolding of the variant proinsulin in the endoplasmic reticulum (ER) of pancreatic β-cells. Clinical mutations are widely distributed in the sequence (86 amino acids). Misfolding induces chronic ER stress and interferes in trans with wildtype biosynthesis and secretion. In the present work we sought to study relative folding efficiencies of proinsulin variants in relation to age of disease onset.

Methods

To enable efficient preparation of non-foldable variants, we developed a four-segment native chemical-ligation scheme that exploits two native cysteines (Cys^B19 and Cys^A6; residues 19 and 71 in proinsulin) and an alanine in the connect

SUBMITTER: Dhayalan B 

PROVIDER: S-EPMC11759498 | biostudies-literature | 2025 Jan

REPOSITORIES: biostudies-literature