Crystal structures and biochemical studies of human lysophosphatidic acid phosphatase type 6

Abstract

Lysophosphatidic acid (LPA) is an important bioactive phospholipid involved in cell signaling through Gprotein-coupled receptors pathways. It is also involved in balancing the lipid composition inside the cell, and modulates the function of lipid rafts as an intermediate in phospholipid metabolism. Because of its involvement in these important processes, LPA degradation needs to be regulated as precisely as its production. Lysophosphatidic acid phosphatase type 6 (ACP6) is an LPA-specifi c acid phosphatase that hydrolyzes LPA to monoacylglycerol (MAG) and phosphate. Here, we report three crystal structures of human ACP6 in complex with malonate, L-(+)-tartrate and tris, respectively. Our analyses revealed that ACP6 possesses a highly conserved Rossmann-foldlike body domain as well as a less conserved cap domain. The vast hydrophobic substrate-binding pocket, which is located between those two domains, is suitable for accommodating LPA, and its shape is different from that of other histidine acid phosphatases, a fact that is consistent with the observed difference in substrate preferences. Our analysis of the binding of three molecules in the active site reveals the involvement of six conserved and crucial residues in binding of the LPA phosphate group and its catalysis. The structure also indicates a water-supplying channel for substrate hydrolysis. Our structural data are consistent with the fact that the enzyme is active as a monomer. In combination with additional mutagenesis and enzyme activity studies, our structural data provide important insights into substrate recognition and the mechanism for catalytic activity of ACP6.

hsa_circ_0013958: a circular RNA and potential novel biomarker for lung adenocarcinoma

“…Our results showed that hsa_circ_0013958 improved cell proliferation and invasion at the same time as inhibiting cell apoptosis. hsa_circ_0013958 is located on chromosome 1q21.2 on the plus strand, and it is aligned in a sense orientation to the known protein‐coding gene ACP6 and spans exon 10 . Until now, the function of hsa_circ_0013958 in tumour development and progression was unknown.…”

Mutant p53 regulates LPA signaling through lysophosphatidic acid phosphatase type 6

“…In this study, we report that mutant p53 upregulates LPA signaling through downregulation of the LPA-degrading enzyme lysophosphatidic acid phosphatase type 6 (ACP6), a lipid phosphate phosphatase. ACP6 is localized to the mitochondria where it plays a role in the regulation of phospholipid levels 22 – 24 . Although ACP6 expression is decreased in esophageal tumors 25 , its potential roles in tumorigenesis and cancer progression have not been functionally investigated.…”

Structure–Function Relationship Study of a Secretory Amoebic Phosphatase: A Computational-Experimental Approach

“…Automatic prediction of the tertiary structure of Eh HAPp49 by homology-based modeling offered additional insights into its three-dimensional (3D) conformation. Using the Eh HAPp49 polypeptide as the query sequence, a restricted BLAST search of the Protein Data Bank (PDB) repository returned the crystal structures of three protein counterparts as suitable templates (E-value < 10 −14 ) for the 3D modeling: (1) the human PAP (prostatic acid phosphatase): 2HPA, 1CVI, 1ND5, and 1ND6 [ 14 , 15 , 16 ], (2) the human LAP (lysophosphatidic acid phosphatase type 6): 4JOB, 4JOC, and 4JOD [ 17 ], and (3) the Legionella pneumophila HAP: 5CDH [ 18 ]. The top five 3D-models generated by the Modeller multi-template approach met the expected structural benchmarks: low normalized discrete optimized protein energy (zDOPE) score and a Ramachandran plot showing more than 85% of residues in the most favored regions.…”