Editors' ChoicePharmacology

Giving protein folding a helping hand

Sci. Signal.  14 Apr 2015:
Vol. 8, Issue 372, pp. ec96
DOI: 10.1126/scisignal.aab3216

The reversible phosphorylation of proteins controls virtually all aspects of cell and organismal function. Targeting phosphorylation offers a broad range of therapeutic opportunities, and kinases have become important therapeutic targets. Phosphatases should be as attractive as kinases as therapeutic targets, but in fact they are more challenging. Das et al. identified a small molecule, Sephin1, that is a specific inhibitor targeting a regulatory subunit of protein phosphatase 1. Sephin1 binds and inhibits PPP1R15A, but not the related regulatory phosphatase PPP1R15B. Sephin1 prolonged a stress-induced, phosphorylation-dependent signaling pathway to prevent the pathological defects in mouse models of two unrelated protein-misfolding diseases Charcot-Marie-Tooth 1B and amyotrophic lateral sclerosis.

I. Das, A. Krzyzosiak, K. Schneider, L. Wrabetz, M. D’Antonio, N. Barry, A. Sigurdardottir, A. Bertolotti, Preventing proteostasis diseases by selective inhibition of a phosphatase regulatory subunit. Science 348, 239–242 (2015). [Abstract] [Full Text]