Substrate specificity of protein tyrosine phosphatase-like myo-inositol phosphatases: PhyA in complex with Ins(1,2,4,5,6)P5, Ins(1,3,4,5)P4, and Ins(1,4,5)P3
Date
2018
Authors
Bruder, Lisza M.
University of Lethbridge. Faculty of Arts and Science
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Lethbridge, Alta. : University of Lethbridge, Department of Chemistry and Biochemistry
Abstract
In order to understand the substrate specificity of protein tyrosine phosphatase-like myo-inositol phosphatases (PTPLPs), I have determined the structure of PhyA from Mitsuokella multacida (PhyAmm) and Selenomonas ruminantium (PhyAsr) in complex with multiple myo-inositol phosphates (IPs). These are the first atomic resolution structures of PTPLPs in complex with InsP5, InsP4, or InsP3 substrates, and represent four of the five known PTPLP:IP complex structures. Based on these structures, I have identified three structural features that determine the substrate specificity of PTPLPs. As part of this work, I demonstrate that the PhyAmm C-terminal repeat and PhyAsr bind substrates using conserved phosphoryl-binding sites. Further, I have determined the InsP6 hydrolysis pathways for several PTPLPs and present a novel IP specificity assay. With this assay, I identify that the two repeats of PhyAmm have divergent activities that clearly indicate a ’divide and conquer’ approach to maximize phosphoryl group removal from InsP6 and mixed IPs.
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Inositol -- Research , Inositol phosphates -- Research , Metabolites -- Research , Enzymes -- Research , Dissertations, Academic , myo-inositol phosphates , phosphoryl-binding , phosphoryl group removal , PhyA , PTPLPs , substrate specificity