Journal article
Insertion of a synthetic switch into insulin provides metabolite-dependent regulation of hormone–receptor activation
YS Chen, J Gleaton, Y Yang, B Dhayalan, NB Phillips, Y Liu, L Broadwater, MA Jarosinski, D Chatterjee, MC Lawrence, T Hattier, M Dodson Michael, MA Weiss
Proceedings of the National Academy of Sciences of the United States of America | NATL ACAD SCIENCES | Published : 2021
Abstract
Insulin-signaling requires conformational change: whereas the free hormone and its receptor each adopt autoinhibited conformations, their binding leads to structural reorganization. To test the functional coupling between insulin’s “hinge opening” and receptor activation, we inserted an artificial ligand-dependent switch into the insulin molecule. Ligand-binding disrupts an internal tether designed to stabilize the hormone’s native closed and inactive conformation, thereby enabling productive receptor engagement. This scheme exploited a diol sensor (meta-fluoro-phenylboronic acid at GlyA1) and internal diol (3,4-dihydroxybenzoate at LysB28). The sensor recognizes monosaccharides (fructose > ..
View full abstractGrants
Awarded by National Institutes of Health
Funding Acknowledgements
We thank M. Otten, G. Pennypacker T. Gray, and A. Hagarman (Thermalin Inc.) for assistance with preparation of biosynthetic insulin analogs; A. Rundell (Thermalin Inc.) for initial biological characterization of FRI analogs; J. Harwood (Director, Purdue NMR Facility) for assistance with preliminary 19F-NMR spectroscopy; D. G. Anderson (Massachusetts Institute of Technology [MIT]), S. Dutta (Juvenile Diabetes Research Foundation [JDRF]), M. F. Ismail-Beigi (Case Western Reserve University [CWRU]), R. Langer (MIT), B. Smith (LaTrobe University), M. Strano (MIT), S. Sullivan (Helmsley Charitable Trust), and J. Whittaker (CWRU) for helpful discussion. M.A.W. acknowledges adjunct/courtesy appointments in the Department of Chemistry at Indiana University (Bloomington) and the Weldon School of Biomedical Engineering at Purdue University and thanks respective colleagues for stimulating discussions and encouragement. Y.-S.C. was supported by a postdoctoral fellowship from the JDRF and a pilot grant from the Diabetes Research Connection. N.B.P. was supported in part by the American Diabetes Association (Grants 7-13-IN-31 and 1-08-RA-149). This work was supported in part by grants from the JDRF, the Leona M. and Harry B. Helmsley Charitable Trust, and the NIH (R01 DK040949 and R01 DK127761). Walter and Eliza Hall Institute of Medical Research (WEHI) received Victorian State Government Operational Infrastructure Support and funding from the Australian National Health and Medical Research Council (NHMRC) Independent Research Institutes Infrastructure Support Scheme.