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“Register-shift” insulin analogs uncover constraints of proteotoxicity in protein evolution by Nischay K. Rege; Ming Liu; Balamurugan Dhayalan; Yen-Shan Chen; Nicholas A. Smith; Leili Rahimi; Jinhong Sun; Huan Guo; Yanwu Yang; Leena Haataja; Nelson F.B. Phillips; Jonathan Whittaker; Brian J. Smith; Peter Arvan; Faramarz Ismail-Beigi; Michael A. Weiss is a Biochemistry, Genetics and Molecular Biology article available to read on EtoBox.

What is “Register-shift” insulin analogs uncover constraints of proteotoxicity in protein evolution about?

Globular protein sequences encode not only functional structures (the native state) but also protein foldability, i.e. a conformational search that is both efficient and robustly minimizes misfolding. Studies of mutations associated with toxic misfolding have yielded insights into molecular determinants of protein foldability. Of particular interest are residues that are conserved yet dispensable in the native state. Here, we exploited the mutant proinsulin syndrome (a major cause of permanent neonatal-onset diabetes mellitus) to investigate whether toxic misfolding poses an evolutionary constraint. Our experiments focused on an invariant aromatic motif (PheB24–PheB25–TyrB26) with complementary roles in native self-assembly and receptor binding. A novel class of mutations provided evidence that insulin can bind to the insulin receptor (IR) in two different modes, distinguished by a “register shift” in this motif, as visualized by molecular dynamics (MD) simulations. Register-shift variants are active but defective in cellular foldability and exquisitely susceptible to fibrillation in vitro. Indeed, expression of the corresponding proinsulin variant induced endoplasmic reticulum str

Who reads “Register-shift” insulin analogs uncover constraints of proteotoxicity in protein evolution?

Author

Nischay K. Rege; Ming Liu; Balamurugan Dhayalan; Yen-Shan Chen; Nicholas A. Smith; Leili Rahimi; Jinhong Sun; Huan Guo; Yanwu Yang; Leena Haataja; Nelson F.B. Phillips; Jonathan Whittaker; Brian J. Smith; Peter Arvan; Faramarz Ismail-Beigi; Michael A. Weiss

Publisher

The American Society for Biochemistry and Molecular Biology; American Society for Biochemistry and Molecular Biology; American Society for Biochemistry and Molecular Biology Inc.; American Society for Biochemistry & Molecular Biology (ASBMB); Elsevier BV (ISSN 0021-9258)

Published

2020

Language

EN

Field

Biochemistry, Genetics and Molecular Biology (Life Sciences)