Bacterial protein tyrosine phosphatase-like myo-inositol phosphatases, PhyA, in complex with the Ins(1,3,4,5)P4 and Ins(1,4,5)P3 second messengers [Enzymology]

Myo-inositol phosphates (IPs) are important bioactive molecules that have multiple activities within eukaryotic cells including well-known roles as second messengers and cofactors that help regulate diverse biochemical processes such as transcription and hormone-receptor activity. Despite the typical absence of IPs in prokaryotes, many of these organisms express IPases (or phytases) that dephosphorylate IPs. Functionally, these enzymes participate in phosphate-scavenging pathways and in plant pathogenesis. Here, we have determined X-ray crystallographic structures of two catalytically inactive mutants of protein tyrosine phosphatase-like myo-inositol phosphatases (PTPLPs) from the non-pathogenic bacteria Selenomonas runimantium (PhyAsr) and Mitsuokella multacida (PhyAmm) in complex with the known eukaryotic second messengers, Ins(1,3,4,5)P4 and Ins(1,4,5)P3. Both enzymes bind these less-phosphorylated IPs in a catalytically-competent manner suggesting IP hydrolysis has a role in plant pathogenesis. The less-phosphorylated IP binding differs in both the myo-inositol ring position and orientation when compared to a previously determined complex structure in the presence of myo-inositol-1,2,3,4,5,6-hexakisphosphate (InsP6 or phytate). Further, we demonstrate that PhyAsr and PhyAmm have different specificities for Ins(1,2,4,5,6)P5, identified structural features that account for this difference and shown that the absence of these features results in a broad specificity towards Ins(1,2,4,5,6)P5. These features are main-chain conformational differences in loops adjacent to the active site that include the extended loop prior to the penultimate helix, the extended Ω-loop and a β-hairpin turn of the Phy-specific domain.

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