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Biochemistry. 2018 Dec 14. doi: 10.1021/acs.biochem.8b01044. [Epub ahead of print]

Molecular architecture of the inositol phosphatase Siw14.

Abstract

Siw14 is a recently discovered inositol phosphatase implicated in suppressing prion propagation in Saccharomyces cerevisiae. In this paper, we used hybrid structural methods to decipher Siw14 molecular architecture. We found the protein exists in solution as an elongate monomer ~140 Å in length, containing an acidic N-terminal domain (NTD) and a basic C-terminal dual specificity phosphatase (DSP) domain, structurally similar to the glycogen phosphatase laforin. The two domains are connected by a protease susceptible linker and do not interact in vitro. The crystal structure of Siw14-DSP reveals a highly basic phosphate-binding loop and a ~10 Å deep substrate-binding crevice evolved to dephosphorylate pyro-phosphate moieties. A pseudo-atomic model of the full-length phosphatase generated from solution, crystallographic, biochemical and modeling data sheds light on the interesting zwitterionic nature of Siw14, which we hypothesized may play a role in discriminating negatively charged inositol phosphates.

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