# Structural Communication Between C-Peptide and Insulin Within the Proinsulin Molecule

## TL;DR

This paper explores how the C-peptide in proinsulin affects insulin production by influencing proinsulin folding and trafficking.

## Contribution

The study reveals that specific C-peptide missense mutations impair proinsulin folding and can interact with wildtype proinsulin.

## Key findings

- Missense mutations in the C-peptide's amino-terminal region impair proinsulin folding and trafficking.
- C-peptide variants physically interact with wildtype proinsulin, altering trafficking based on expression ratios.
- The C-peptide's amino-terminal portion plays a role in human insulin biogenesis.

## Abstract

Despite years of study, the biological role of the human proinsulin connecting peptide (C-peptide) remains poorly understood. Nevertheless, the C-peptide exhibits subdomains including conserved residues that are thought to have co-evolved with the insulin moiety of proinsulin. Genome-wide association studies in humans suggest that alterations of glycemic control may exhibit a possible linkage with the presence of certain C-peptide variants other than frame-shifts, stop codons, alternative splice variants, or the addition of an extra unpaired Cys residue. Although the C-peptide is ultimately excised from insulin, here, we have bioengineered missense mutations in the amino-terminal portion of the C-peptide (especially involving or near preproinsulin residues Q62,V63) that we find impair proinsulin folding and trafficking efficiency and, in this way, impair insulin biogenesis. We show that proinsulin bearing a C-peptide missense variant can also physically interact with co-expressed wildtype proinsulin, affecting the trafficking behavior of both proinsulin proteins in a manner that is directly related to the relative expression ratio of the variant and wildtype gene products. We conclude that in addition to other possible functions, the amino-terminal portion of the C-peptide influences proinsulin folding and trafficking and, in this way, affects human insulin production.