The Structure and Function of Acylglycerophosphate Acyltransferase 4/ Lysophosphatidic Acid Acyltransferase Delta (AGPAT4/LPAATδ)

Abstract

Lipid-modifying enzymes serve crucial roles in cellular processes such as signal transduction (producing lipid-derived second messengers), intracellular membrane transport (facilitating membrane remodeling needed for membrane fusion/fission), and protein clustering (organizing lipid domains as anchoring platforms). The lipid products crucial in these processes can derive from different metabolic pathways, thus it is essential to know the localization, substrate specificity, deriving products (and their function) of all lipid-modifying enzymes. Here we discuss an emerging family of these enzymes, the lysophosphatidic acid acyltransferases (LPAATs), also known as acylglycerophosphate acyltransferases (AGPATs), that produce phosphatidic acid (PA) having as substrates lysophosphatidic acid (LPA) and acyl-CoA. Eleven LPAAT/AGPAT enzymes have been identified in mice and humans based on sequence homologies, and their localization, specific substrates and functions explored. We focus on one member of the family, LPAATδ, a protein expressed mainly in brain and in muscle (though to a lesser extent in other tissues); while at the cellular level it is localized at the trans- Golgi network membranes and at the mitochondrial outer membranes. LPAATδ is a physiologically essential enzyme since mice knocked-out for Lpaatδ show severe dysfunctions including cognitive impairment, impaired force contractility and altered white adipose tissue. The LPAATδ physiological roles are related to the formation of its product PA. PA is a multifunctional lipid involved in cell signaling as well as in membrane remodeling. In particular, the LPAATδ-catalyzed conversion of LPA (inverted-cone-shaped lipid) to PA (cone-shaped lipid) is considered a mechanism of deformation of the bilayer that favors membrane fission. Indeed, LPAATδ is an essential component of the fission-inducing machinery driven by the protein BARS. In this process, a protein-tripartite complex (BARS/14-3-3γ/phosphoinositide kinase PI4KIIIβ) is recruited at the trans -Golgi network, at the sites where membrane fission is to occur; there, LPAATδ directly interacts with BARS and is activated by BARS. The resulting formation of PA is essential for membrane fission occurring at those spots. Also in mitochondria PA formation has been related to fusion/fission events. Since PA is formed by various enzymatic pathways in different cell compartments, the BARS-LPAATδ interaction indicates the relevance of lipid-modifying enzymes acting exactly where their products are needed (i.e., PA at the Golgi membranes).

New Era of Diacylglycerol Kinase, Phosphatidic Acid and Phosphatidic Acid-Binding Protein

“…Lysophosphatidic acid acyltransferase (LPAAT) also generates various PA species ( Figure 1 ), which are basically utilized as precursors of various phospholipids. Interestingly, there are several LPAAT isozymes that can add different fatty acids to LPA [ 277 , 278 , 279 ]. PLD- and LPAAT-derived PA species, which can also bind to PA species-selective PABP, together with DGK-derived PA species would confer complexity to the PA molecular species-signaling network.…”

Protein Amphipathic Helix Insertion: A Mechanism to Induce Membrane Fission

“…Class II: Passive mechanism, normal topology. Examples: fission mediated, in the absence of nucleoside triphosphate hydrolysis, by Bacillus subtilis FisB (Doan et al, 2013), C-terminal Binding Protein 1 Short form/Brefeldin A ADP-Ribosylation substrate (CtBP1-S/BARS) (Spanò et al, 1999;Weigert et al, 1999;Hidalgo Carcedo et al, 2004;Valente et al, 2005Valente et al, , 2012Liberali et al, 2008;Pagliuso et al, 2016;Zhukovsky et al, 2019b), and by numerous AH-containing proteins, such as endophilins (Rostovtseva et al, 2009;Ambroso et al, 2014;Genet et al, 2019), amphiphysins (Wu and Baumgart, 2014;Snead et al, 2019), epsins (Ford et al, 2002;Boucrot et al, 2012;Brooks et al, 2015), α-synuclein (Nakamura et al, 2011;Braun et al, 2017;Pozo Devoto and Falzone, 2017;Fakhree et al, 2019), GDAP1 (Huber et al, 2016), ankyrin repeats and KH domain-containing protein 1 (ANKHD1) (Kitamata et al, 2019), Saccharomyces cerevisiae Atg18 (Gopaldass et al, 2017), Agrobacterium tumefaciens PmtA (Danne et al, 2017b), EcMurG (van den Brink-van der Laan et al, 2003, Acholeplasma laidlawii MGS (Eriksson et al, 2009;Ariöz et al, 2014;Ge et al, 2014) and DGS (Eriksson et al, 2009).…”

“…Interestingly, two fission-inducing proteins, A. tumefaciens PmtA and mammalian CtBP1-S/BARS, are known to play a role in the synthesis of their own lipid cofactors. The difference between PmtA and CtBP1-S/BARS is that PmtA is itself an enzyme that produces its own lipid cofactor MMPE (Danne et al, 2017b), whereas CtBP1-S/BARS binds to and activates an enzyme, LPAATδ that catalyzes the synthesis of PA required for CtBP1-S/BARS-mediated membrane fission (Pagliuso et al, 2016;Zhukovsky et al, 2019b). Such production of lipid cofactors promoted by the very fission-inducing proteins and then using them guarantees availability of these lipids where and when they are needed.…”

Phosphatidic acid in membrane rearrangements

“… de novo synthesis pathway in which the final step is acylation of LPA by lysophosphatidic acid acyltransferases (LPAATs) . Five members of LPAAT family are present in mammals .…”