The structure of the RCAN1:CN complex explains the inhibition of and substrate recruitment by calcineurin
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Univ Arizona, Dept Chem & BiochemIssue Date
2020-07-01
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AMER ASSOC ADVANCEMENT SCIENCECitation
Li, Y., Sheftic, S. R., Grigoriu, S., Schwieters, C. D., Page, R., & Peti, W. (2020). The structure of the RCAN1:CN complex explains the inhibition of and substrate recruitment by calcineurin. Science advances, 6(27), eaba3681.Journal
SCIENCE ADVANCESRights
Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).Collection Information
This item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at repository@u.library.arizona.edu.Abstract
Regulator of calcineurin 1 (RCAN1) is an endogenous inhibitor of the Ser/Thr phosphatase calcineurin (CN). It has been shown that excessive inhibition of CN is a critical factor for Down syndrome and Alzheimer's disease. Here, we determined RCAN1's mode of action. Using a combination of structural, biophysical, and biochemical studies, we show that RCAN1 inhibits CN via multiple routes: first, by blocking essential substrate recruitment sites and, second, by blocking the CN active site using two distinct mechanisms. We also show that phosphorylation either inhibits RCAN1-CN assembly or converts RCAN1 into a weak inhibitor, which can be reversed by CN via dephosphorylation. This highlights the interplay between posttranslational modifications in regulating CN activity. Last, this work advances our understanding of how active site inhibition of CN can be achieved in a highly specific manner. Together, these data provide the necessary road map for targeting multiple neurological disorders.Note
Open access journalISSN
2375-2548Version
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National Institute of General Medical Sciencesae974a485f413a2113503eed53cd6c53
10.1126/sciadv.aba3681
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Except where otherwise noted, this item's license is described as Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).