Unraveling C-Peptide’s Role in MIDY: A Structural Perspective Proinsulin folding requires dynamic positioning of the C-peptide to guide A- and B-chain alignment and disulfide pairing. Mutant INS-gene-induced diabetes of youth (MIDY) arises when single-residue substitutions disrupt this process. We mapped the conformational free-energy landscapes of wild-type (WT) proinsulin and seven MIDY variants using metadynamics and molecular dynamics simulations. WT exhibits a deep free-energy minimum at compact conformations. In contrast, MIDY mutants display a continuum of destabilization: E(A4)K retains near-WT stability, Akita (C(A7)Y), V(B18)A, and R(Cpep + 2)C show moderate loss of the native basin, while H(B5)D, L(A16)P, and Y(B26)C collapse the closed–open barrier and populate misfolded open states >50% of the time. Structural analyses reveal that WT and E(A4)K preserve robust A–C docking, with the C-peptide flexibly engaging the A-chain groove. Destabilizing mutants progressively erode these native A–C contacts while forming compensatory, non-native B–C interactions. Per-residue energy decomposition highlights the loss of canonical salt bridges and emergence of aberrant electrostatic and hydrophobic hot spots, correlating with the collapse of the folding free-energy barrier. Secondary-structure analysis further shows that mutants rigidify the normally disordered C-peptide, increasing helical or strand propensity in a mutation-specific manner. Collectively, these findings establish a continuum from near-native stability to overt misfolding, mechanistically linking single-site mutations to altered folding landscapes and aggregation risk in MIDY. The results highlight the C-peptide as a dynamic linchpin of proinsulin folding and suggest that restoring its flexible docking could provide a therapeutic avenue.

New from our group: Unraveling C-Peptide’s Role in MIDY: A Structural Perspective | ACS Omega pubs.acs.org/doi/10.1021/...

Congratulations @sranga88.bsky.social and my lab folks! 🎉

#proteinfolding #proinsulin #mutations #Cpeptide #structuralbiology #computationalbiology #MDsimulations

Ca2+-driven PDIA6 biomolecular condensation ensures proinsulin folding - Nature Cell Biology Lee et al. show that Ca²⁺ triggers condensates enriched with PDIA6, an ER-resident disulfide isomerase and chaperone, along with other protein disulfide isomerase family proteins and some chaperones t...

☕Lee et al. show that Ca²⁺ triggers condensates enriched with PDIA6, an ER-resident disulfide isomerase and chaperone, along with other protein disulfide isomerase family proteins and some chaperones that in turn enhance folding of #proinsulin. #PhaseSeparation
bit.ly/44mX1bW

TBC1D30 regulates proinsulin and insulin secretion and is the target of a genomic association signal for proinsulin - Diabetologia Aims/hypothesis Components of the insulin processing and secretion pathways remain incompletely understood. Here, we examined a genome-wide association study (GWAS) signal for plasma proinsulin levels...

TBC1D30 sequence & expression changes impact proinsulin & insulin secretion, linking this putative RabGAP to GWAS signal for proinsulin levels. Study suggests role for TBC1D30 in proinsulin secretion & diabetes risk. #T2D #Proinsulin #GWAS #PrimeEditing link.springer.com/article/10.1...

Frontiers | Exploring proinsulin proteostasis: insights into beta cell health and diabetes

Our first article on proinsulin proteostasis from ETSU. 😊
www.frontiersin.org/journals/mol...
Testament to great efforts by undergraduate students in my lab! 🙋🏻‍♂️
#proteinfolding #diabetes #proteinaggregation #insulin #proinsulin #ERqualitycontrol #proteostasis

Research Article: Proinsulin folding and trafficking defects trigger a common pathological disturbance of endoplasmic reticulum homeostasis -Protein Science

#proteinaggregation #misfolding #proteinfolding #proinsulin #disulfidebonds #betacells #Diabetes

onlinelibrary.wiley.com/doi/full/10....