A Structural Exposé of Noncanonical Molecular Reactivity Within the Protein Tyrosine Phosphatase WPD Loop

Overview

Journal Nat Commun

Specialty Biology

Date 2022 Apr 26

PMID 35468885

Authors

Huanchen Wang

Lalith Perera

Nikolaus Jork

Guangning Zong

Andrew M Riley

Barry V L Potter

Henning J Jessen

Stephen B Shears

Affiliations

Soon will be listed here.

Abstract

Structural snapshots of protein/ligand complexes are a prerequisite for gaining atomic level insight into enzymatic reaction mechanisms. An important group of enzymes has been deprived of this analytical privilege: members of the protein tyrosine phosphatase (PTP) superfamily with catalytic WPD-loops lacking the indispensable general-acid/base within a tryptophan-proline-aspartate/glutamate context. Here, we provide the ligand/enzyme crystal complexes for one such PTP outlier: Arabidopsis thaliana Plant and Fungi Atypical Dual Specificity Phosphatase 1 (AtPFA-DSP1), herein unveiled as a regioselective and efficient phosphatase towards inositol pyrophosphate (PP-InsP) signaling molecules. Although the WPD loop is missing its canonical tripeptide motif, this structural element contributes to catalysis by assisting PP-InsP delivery into the catalytic pocket, for a choreographed exchange with phosphate reaction product. Subsequently, an intramolecular proton donation by PP-InsP substrate is posited to substitute functionally for the absent aspartate/glutamate general-acid. Overall, we expand mechanistic insight into adaptability of the conserved PTP structural elements.

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