Giving protein folding a helping hand

The reversible phosphorylation of proteins controls virtually all aspects of cell and organismal function. Targeting phosphorylation offers a broad range of therapeutic opportunities, and thus kinases have become important therapeutic targets. As targets, phosphatases should be as attractive, but in fact they are more challenging to manipulate. Das et al. have found a safe and specific inhibitor, called Sephin1, that targets a regulatory subunit of protein phosphatase 1 in vivo. Sephin1 binds and inhibits PPP1R15A, but not the related regulatory phosphatase PPP1R15B. In mice, Sephin1 prolonged a stress-induced phospho-signaling pathway to prevent the pathological defects of the unrelated protein-misfolding diseases Charcot-Marie-Tooth 1B and amyotrophic lateral sclerosis.
Science, this issue p. 239


Protein phosphorylation regulates virtually all biological processes. Although protein kinases are popular drug targets, targeting protein phosphatases remains a challenge. Here, we describe Sephin1 (selective inhibitor of a holophosphatase), a small molecule that safely and selectively inhibited a regulatory subunit of protein phosphatase 1 in vivo. Sephin1 selectively bound and inhibited the stress-induced PPP1R15A, but not the related and constitutive PPP1R15B, to prolong the benefit of an adaptive phospho-signaling pathway, protecting cells from otherwise lethal protein misfolding stress. In vivo, Sephin1 safely prevented the motor, morphological, and molecular defects of two otherwise unrelated protein-misfolding diseases in mice, Charcot-Marie-Tooth 1B, and amyotrophic lateral sclerosis. Thus, regulatory subunits of phosphatases are drug targets, a property exploited here to safely prevent two protein misfolding diseases.

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Supplementary Material


Materials and Methods
Figs. S1 to S6
References (2629)


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References and Notes

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Published In

Volume 348 | Issue 6231
10 April 2015

Submission history

Received: 8 December 2014
Accepted: 6 March 2015
Published in print: 10 April 2015


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We thank P. Tsaytler for some initial experiments on Sephin1; H. Meziane for the studies on memory; E. Fisher for SOD1G93A mice; E. Pettinato and C. Ferri for technical assistance; R. Roberts for discussions on CMT; A. Segonds-Pichon for statistical analysis; and members of the Bertolotti laboratory, M. Goedert, M. Hastings, and S. Munro for discussions. A.B. is an honorary fellow of the Clinical Neurosciences Department of Cambridge University. This work was supported by the Medical Research Council (UK) and the European Research Council (ERC) under the European Union’s Seventh Framework Programme (FP7/2007-2013)/ERC grant 309516. A.K. was supported by the European Molecular Biology Organization and Human Frontier Science Program, K.S. by the Swiss National Science Foundation, M.D. by the Italian Ministry of Health (GR-2011-02642791), and L.W. by NIH R01-NS55256. A.B. is a co-inventor on Great Britain patent WO 2014108520, covering benzylideneguanidine derivatives inhibitors of PPP1R15A. The data presented in this paper are tabulated in the main paper and the supplementary materials.



Indrajit Das
Medical Research Council Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge, CB2 0QH, UK.
Agnieszka Krzyzosiak
Medical Research Council Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge, CB2 0QH, UK.
Kim Schneider
Medical Research Council Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge, CB2 0QH, UK.
Lawrence Wrabetz
Division of Genetics and Cell Biology, San Raffaele Scientific Institute, 20132 Milan, Italy.
Present address: Hunter James Kelly Research Institute (HJKRI), University at Buffalo School of Medicine and Biomedical Sciences, 701 Ellicott Street, Buffalo, NY 14203, USA.
Maurizio D’Antonio
Division of Genetics and Cell Biology, San Raffaele Scientific Institute, 20132 Milan, Italy.
Nicholas Barry
Medical Research Council Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge, CB2 0QH, UK.
Anna Sigurdardottir
Medical Research Council Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge, CB2 0QH, UK.
Anne Bertolotti [email protected]
Medical Research Council Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge, CB2 0QH, UK.


Corresponding author. E-mail: [email protected]

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