Phosphatidic acid – a simple phospholipid with multiple faces

Abstract

Phosphatidic acid (PA) is the simplest glycerophospholipid naturally occurring in living organisms, and even though its content among other cellular lipids is minor, it is drawing more and more attention due to its multiple biological functions. PA is a precursor for other phospholipids, acts as a lipid second messenger and, due to its structural properties, is also a modulator of membrane shape. Although much is known about interaction of PA with its effectors, the molecular mechanisms remain unresolved to a large degree. Throughout many of the well-characterized PA cellular sensors, no conserved binding domain can be recognized. Moreover, not much is known about the cellular dynamics of PA and how it is distributed among subcellular compartments. Remarkably, PA can play distinct roles within each of these compartments. For example, in the nucleus it behaves as a mitogen, influencing gene expression regulation, and in the Golgi membrane it plays a role in membrane trafficking. Here, we discuss how a biophysical experimental approach enabled PA behavior to be described in the context of a lipid bilayer and to what extent various physicochemical conditions may modulate the functional properties of this lipid. Understanding these aspects would help to unravel specific mechanisms of PA-driven membrane transformations and protein recruitment and thus would lead to a clearer picture of the biological role of PA.

Phosphatidic acid in membrane rearrangements

“…At least 50 proteins that bind to PA or are regulated by PA were found in yeast, plants and animals . However, no PA‐recognition consensus sequence motif was identified so far in a contrast to the known lipid‐binding domains, such as Pleckstrin Homology (PH), Phox ( ph agocyte ox idase) Homology (PX), Fab 1‐YOTB‐Vac 1‐EEA1 (FYVE), or second conserved domain of protein kinase C (C2) domains. According to the current view, such motif does not exist; PA effectors use cationic and/or surface exposed hydrophobic residues for binding to PA .…”

“…In lysophosphatidic acid (LPA), or 1‐acyl‐ sn ‐glycero‐3‐phosphate, only one fatty acid is bonded to carbon‐1. PA is a minor membrane phospholipid, it usually constitutes 1‐4% of membrane lipids . However, this substance is present in virtually all cellular membranes ( and references therein).…”

“…One of these pathways is the reduction of DHAP to glycerol‐3‐phosphate (G3P) via glycerol‐3‐phosphate dehydrogenase (GPDH), followed by the acylation of G3P to LPA via glycerol‐3‐phosphate acyltransferase (GPAT) . Another pathway is the acylation of DHAP to 1‐acyl‐DHAP (Ac‐DHAP) via DHAP acyltransferase (DHAP AT), followed by the reduction of Ac‐DHAP to LPA via Ac‐DHAP reductase . the phosphorylation of diacylglycerol (DAG) by diacylglycerol kinases (DGKs) . Ten members of DGK family are known ( and references therein); hydrolysis of phospholipids by phospholipase D (PLD) .…”

“…In turn, PA can be metabolized to DAG by phosphatidic acid phosphatases (PAPs) or to LPA by phospholipase A (PLA 1 and PLA 2 ) . In plant and yeast cells, PA can be phosphorylated by PA kinase (PAK) into diacylglycerolpyrophosphate (DAGPP), and PA can be produced from DAGPP by DPP (DAGPP phosphatase) . Hence, directly or indirectly, PA is involved in biosynthesis and homeostasis of most phospholipids .…”

“…In lysophosphatidic acid (LPA), or 1-acyl-sn-glycero-3phosphate, only one fatty acid is bonded to carbon-1. PA is a minor membrane phospholipid, it usually Abbreviations AGPAT4, acylglycerophosphate acyltransferase type 4; C2 domain, second conserved domain of protein kinase C; Cer-1-P, ceramide-1-phosphate; CtBP1-S/BARS, C-terminal-binding protein 1-short form/brefeldin A ADP-ribosylation substrate; DAG, diacylglycerol; DAGPP, diacylglycerolpyrophosphate; DGKs, diacylglycerol kinases; DHAP, dihydroxyacetone phosphate; DOPC, dioleoyl phosphatidylcholine; Drp1, dynamin-related protein 1; EEA1, Early Endosome Antigen 1; F-BAR domain, FCH-Bin/amphiphysin/RVS domain; FYVE domain, Fab 1-YOTB-Vac 1-EEA1 domain; G3P, glycerol-3-phosphate; LPA, lysophosphatidic acid; LPAAT, lysophosphatidic acid acyltransferase; LPC, lysophosphatidylcholine; MICAL-L1, molecule interacting with CasL-Like1; Munc13, mammalian uncoordinated 13; NSF, N-ethylmaleimide-sensitive factor; PA, phosphatidic acid; Pah1, phosphatidic acid phosphatase 1; PAK, p21-activated kinase; PAP, phosphatidic acid phosphatase; PA-PLA1, phosphatidic acid-selective phospholipase A1; PC, phosphatidylcholine; PE, phosphatidylethanolamine; PG, phosphatidylglycerol; PH domain, Pleckstrin Homology domain; PI, phosphatidylinositol; PIPs, phosphatidylinositol phosphates; PKCs, protein kinases C; PKDs, protein kinases D; PLA, phospholipase A; PLD, phospholipase D; PS, phosphatidylserine; PtdIns(4,5)P 2 , phosphatidylinositol-4,5-bisphosphate; PtdIns4P, phosphatidylinositol-4-phosphate; PtdIns4P5K, phosphatidylinositol-4-phosphate-5-kinase; PX domain, phox (phagocyte oxidase) homology domain; RasGRPs, Ras guanyl nucleotide-releasing proteins; SNARE, soluble N-ethylmaleimide-sensitive factor attachment protein receptor; TGN, trans-Golgi network; Unc-13, uncoordinated protein 13; Vps1p, vacuolar protein sorting-associated protein 1. constitutes 1-4% of membrane lipids [2][3][4][5][6]. However, this substance is present in virtually all cellular membranes ( [7] and references therein).…”