Protective hinge in insulin opens to enable its receptor engagement
- Author(s)
- Menting, JG; Yang, Y; Chan, SJ; Phillips, NB; Smith, BJ; Whittaker, J; Wickramasinghe, NP; Whittaker, LJ; Pandyarajan, V; Wan, ZL; Yadav, SP; Carroll, JM; Strokes, N; Roberts, CT, Jr; Ismail-Beigi, F; Milewski, W; Steiner, DF; Chauhan, VS; Ward, CW; Weiss, MA; Lawrence, MC;
- Details
- Publication Year 2014-08-19,Volume 111,Issue #33,Page E3395-404
- Journal Title
- Proceedings of the National Academy of Sciences of the United States of America
- Publication Type
- Journal Article
- Abstract
- Insulin provides a classical model of a globular protein, yet how the hormone changes conformation to engage its receptor has long been enigmatic. Interest has focused on the C-terminal B-chain segment, critical for protective self-assembly in beta cells and receptor binding at target tissues. Insight may be obtained from truncated "microreceptors" that reconstitute the primary hormone-binding site (alpha-subunit domains L1 and alphaCT). We demonstrate that, on microreceptor binding, this segment undergoes concerted hinge-like rotation at its B20-B23 beta-turn, coupling reorientation of Phe(B24) to a 60 degrees rotation of the B25-B28 beta-strand away from the hormone core to lie antiparallel to the receptor's L1-beta2 sheet. Opening of this hinge enables conserved nonpolar side chains (Ile(A2), Val(A3), Val(B12), Phe(B24), and Phe(B25)) to engage the receptor. Restraining the hinge by nonstandard mutagenesis preserves native folding but blocks receptor binding, whereas its engineered opening maintains activity at the price of protein instability and nonnative aggregation. Our findings rationalize properties of clinical mutations in the insulin family and provide a previously unidentified foundation for designing therapeutic analogs. We envisage that a switch between free and receptor-bound conformations of insulin evolved as a solution to conflicting structural determinants of biosynthesis and function.
- Publisher
- National Academy of Sciences
- Research Division(s)
- Structural Biology
- Publisher's Version
- https://doi.org/10.1073/pnas.1412897111
- Terms of Use/Rights Notice
- Copyright © 2014 National Academy of Sciences.
Creation Date: 2014-09-12 02:01:43