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Structure of lipid phosphate phosphatase PgpB complex with PE
Structural highlights
FunctionPGPB_ECOLI Catalyzes the dephosphorylation of diacylglycerol diphosphate (DGPP) to phosphatidate (PA) and the subsequent dephosphorylation of PA to diacylglycerol (DAG). Also has undecaprenyl pyrophosphate phosphatase activity, required for the biosynthesis of the lipid carrier undecaprenyl phosphate. Can also use lysophosphatidic acid (LPA) and phosphatidylglycerophosphate as substrates. The pattern of activities varies according to subcellular location, PGP phosphatase activity is higher in the cytoplasmic membrane, whereas PA and LPA phosphatase activities are higher in the outer membrane. Activity is independent of a divalent cation ion and insensitive to inhibition by N-ethylmaleimide.[1] [2] [3] [4] Publication Abstract from PubMedPgpB belongs to the lipid phosphate phosphatase protein family and is one of three bacterial integral membrane phosphatases catalyzing dephosphorylation of phosphatidylglycerol-phosphate (PGP) to generate PG. Although the structure of its apo form became recently available, the mechanisms of PgpB substrate binding and catalysis are still unclear. We found that PgpB was inhibited by phosphatidylethanolamine (PE) in a competitive mode in vitro Here we report the crystal structure of the lipid-bound form of PgpB. The structure shows that a PE molecule is stabilized in a membrane-embedded tunnel formed by TM3 and the PSGH fingerprint peptide near the catalytic site, providing structural insight into PgpB substrate binding mechanism. Noteworthy, in silico docking of varied lipid phosphates exhibited similar substrate binding modes to that of PE and the residues in the lipid tunnel appear to be important for PgpB catalysis. The catalytic triad in the active site is essential for dephosphorylating substrates LPA, PA or S1P but surprisingly not for the native substrate PGP. Remarkably, residue H207 alone is sufficient to hydrolyze PGP, indicating a specific catalytic mechanism for PgpB in PG biosynthesis. We also identified two novel sensor residues, K93 and K97, on TM3. Our data show that K97 is essential for the recognition of lyso form substrates. Modification at the K93 position may alter substrate specificity of LPPs in prokaryotes vs eukaryotes. These studies reveal new mechanisms of lipid substrate selection and catalysis by PgpB and suggest that the enzyme rests in a PE-stabilized state in the bilayer. Structural insight into substrate selection and catalysis of lipid phosphate phosphatase PgpB in the cell membrane.,Tong S, Lin Y, Lu S, Wang M, Bogdanov M, Zheng L J Biol Chem. 2016 Jul 12. pii: jbc.M116.737874. PMID:27405756[5] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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