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A Structural Basis for Lithium and Substrate Binding of an Inositide Phosphatase


Dollins DED. Eric , Xiong JJian-Ping , Endo-Streeter SStuart , Anderson DDavid , Bansal VVinay , Ponder JJay , Ren YYi , York JDJohn . Journal of Biological Chemistry. 2020 11 10; ().


Inositol polyphosphate 1-phosphatase (INPP1) is a prototype member of metal-dependent/lithium-inhibited phosphomonoesterase protein family defined by a conserved three-dimensional core structure. Enzymes within this family function in distinct pathways including: inositide signaling, gluconeogenesis, and sulfur assimilation. Using structural and biochemical studies, we report the effect of substrate and lithium on a network of metal binding sites within the catalytic center of INPP1. We find that lithium preferentially occupies a key site involved in metal-activation only when substrate or product is added. Mutation of a conserved residue that selectively coordinates the putative lithium-binding site results in a dramatic 100-fold reduction in the inhibitory constant as compared to wild-type. Furthermore, we report the INPP1/inositol 1,4-bisphosphate complex which illuminates key features of the enzyme active site. Our results provide insights into a structural basis for uncompetitive lithium inhibition, substrate recognition and define a sequence motif for metal binding within this family of regulatory phosphatases.