Role of Proinsulin Self-Association in Mutant INS Gene-Induced Diabetes of Youth.

Diabetes
Jinhong SunMing Liu

Abstract

Abnormal interactions between misfolded mutant and wild-type (WT) proinsulin (PI) in the endoplasmic reticulum (ER) drive the molecular pathogenesis of mutant INS gene-induced diabetes of youth (MIDY). How these abnormal interactions are initiated remains unknown. Normally, PI-WT dimerizes in the ER. Here, we suggest that the normal PI-PI contact surface, involving the B-chain, contributes to dominant-negative effects of misfolded MIDY mutants. Specifically, we find that PI B-chain tyrosine-16 (Tyr-B16), which is a key residue in normal PI dimerization, helps confer dominant-negative behavior of MIDY mutant PI-C(A7)Y. Substitutions of Tyr-B16 with either Ala, Asp, or Pro in PI-C(A7)Y decrease the abnormal interactions between the MIDY mutant and PI-WT, rescuing PI-WT export, limiting ER stress, and increasing insulin production in β-cells and human islets. This study reveals the first evidence indicating that noncovalent PI-PI contact initiates dominant-negative behavior of misfolded PI, pointing to a novel therapeutic target to enhance PI-WT export and increase insulin production.

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Citations

Jan 20, 2021·The Journal of Clinical Investigation·Ming LiuPeter Arvan
Nov 7, 2020·Proceedings of the National Academy of Sciences of the United States of America·Nischay K RegeMichael A Weiss
Apr 7, 2021·Molecular Metabolism·Balamurugan DhayalanMichael A Weiss
Jul 11, 2021·Cellular and Molecular Life Sciences : CMLS·Leena HaatajaPeter Arvan
Jul 20, 2021·Physiological Reviews·Adam Ramzy, Timothy J Kieffer
Oct 19, 2021·Frontiers in Endocrinology·Balamurugan DhayalanMichael A Weiss

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