期刊
NATURE COMMUNICATIONS
卷 13, 期 1, 页码 -出版社
NATURE PORTFOLIO
DOI: 10.1038/s41467-022-29673-y
关键词
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资金
- Intramural Research Program of the NIH, National Institute of Environmental Health Sciences
- German Research Foundation (DFG) under Germany's Excellence Strategy [CIBSS - EXC-2189, 390939984, JE 572/4-1]
- Wellcome Trust
This study provides the analysis of ligand/enzyme crystal complexes for Arabidopsis thaliana Plant and Fungi Atypical Dual Specificity Phosphatase 1 (AtPFA-DSP1), uncovering its regioselective and efficient phosphatase activity towards inositol pyrophosphate (PP-InsP) signaling molecules. Despite lacking the traditional tripeptide motif, the WPD loop structural element still contributes to catalysis by assisting with the delivery of PP-InsP into the catalytic pocket. Functionally, it is proposed that the substrate PP-InsP substitutes for the absent aspartate/glutamate general-acid through intramolecular proton donation.
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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