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, 1862 (11), 1404-1413

Biogenesis, Transport and Remodeling of Lysophospholipids in Gram-negative Bacteria


Biogenesis, Transport and Remodeling of Lysophospholipids in Gram-negative Bacteria

Lei Zheng et al. Biochim Biophys Acta Mol Cell Biol Lipids.


Lysophospholipids (LPLs) are metabolic intermediates in bacterial phospholipid turnover. Distinct from their diacyl counterparts, these inverted cone-shaped molecules share physical characteristics of detergents, enabling modification of local membrane properties such as curvature. The functions of LPLs as cellular growth factors or potent lipid mediators have been extensively demonstrated in eukaryotic cells but are still undefined in bacteria. In the envelope of Gram-negative bacteria, LPLs are derived from multiple endogenous and exogenous sources. Although several flippases that move non-glycerophospholipids across the bacterial inner membrane were characterized, lysophospholipid transporter LplT appears to be the first example of a bacterial protein capable of facilitating rapid retrograde translocation of lyso forms of glycerophospholipids across the cytoplasmic membrane in Gram-negative bacteria. LplT transports lyso forms of the three bacterial membrane phospholipids with comparable efficiency, but excludes other lysolipid species. Once a LPL is flipped by LplT to the cytoplasmic side of the inner membrane, its diacyl form is effectively regenerated by the action of a peripheral enzyme, acyl-ACP synthetase/LPL acyltransferase (Aas). LplT-Aas also mediates a novel cardiolipin remodeling by converting its two lyso derivatives, diacyl or deacylated cardiolipin, to a triacyl form. This coupled remodeling system provides a unique bacterial membrane phospholipid repair mechanism. Strict selectivity of LplT for lyso lipids allows this system to fulfill efficient lipid repair in an environment containing mostly diacyl phospholipids. A rocker-switch model engaged by a pair of symmetric ion-locks may facilitate alternating substrate access to drive LPL flipping into bacterial cells. This article is part of a Special Issue entitled: Bacterial Lipids edited by Russell E. Bishop.

Keywords: Bacterial lipid; Flippase; LplT; Lysophospholipid; Membrane; Remodeling.


Fig. 1
Fig. 1. Routes of lysophospholipid biogenesis and remodeling in the Gram-negative bacterial envelope
Lysophospholipids are generated in the periplasm. In the OM, [1] activated PldA hydrolyzes a PE to generate LPE; [2] PagP catalyzes the transfer of a palmitoyl group from a PE to lipid A, generating hepta-acylated lipid A and LPE as by-product. In the IM, [3] Lnt transfers the fatty acid moiety from PE to the N terminus of a major outer membrane lipoprotein precursor (Lpp), generating a triacylated mature Lpp and releasing LPE as by-product. LPL can be generated by membrane degradation mediated by [4] exogenous sPLA2 and BPI from the host or by [5] the Tle protein delivered from invading bacteria via the type VI secretion system (T6S). The generated LPLs are translocated by LplT [6] from the outer leaflet to the inner leaflet of the IM where they can be reacylated by the coupled acyltransferase Aas.
Fig. 2
Fig. 2. Architectural scheme of the LplT-Aas system in Gram-negative bacteria.
Panel a, five classes of the LplT-Aas system in different Gram-negative bacterial genomes. Panel b & c, Membrane topology of LplT or Aas from Escherichia coli predicted by the TMHMM server (89). The LplT protein is predicted to have ten transmembrane helices. The Aas protein contains two tandem domains, the N-terminal acyltransferase (PlsC) domain and the C-terminal acyl-ACP synthetase (ACS) domain. Two hydrophobic segments were predicted in the ACS domain.
Fig. 3
Fig. 3. Scheme of lysophospholipid remodeling mediated by the LplT-Aas system.
LplT substrates LPE, LPG, diacyl-CL and deacylated CL (CL-hg) are transported by LplT from the periplasm to the inner leaflet of the IM by an energy-independent mechanism. On the cytoplasmic surface, bifunctional Aas catalyzes acyl transfer to a flipped LPL using acyl-ACP as acyl donor, generating PE, PG or triacyl-CL respectively. Aas also catalyzes ATP-dependent synthesis of acyl-ACP using a fatty acid. LPA, LPC and glycerol-3-phosphate (G3P) are not LplT substrates.
Fig. 4
Fig. 4. Hypothetical model of the LplT-mediated lysophospholipid transport mechanism.
Panel a, Secondary structure of LplT showing the locations of the conserved residues in the putative substrate translocation pathway. The transmembrane topology diagram was rendered based on a structural homolog model of LplT from Klebsiella pneumonia generated previously (16), showing twelve transmembrane helices (–12). Individual amino acids are represented by circles, with negatively charged residues in red, positively charged residues in blue, and other polar residues in green. The residues predicted to form the periplasmic binding site, the shuttle site and the cytoplasmic binding site are surrounded by dashed lines, respectively. Panel b, a hypothetical rocker-switch model for LplT-mediated LPL transport. The N-terminal domain formed by helices 1–6 and C-terminal domain formed by helices 7–12 of LplT are colored in green and yellow, respectively. The following three-step mechanism is proposed for LplT transport: i) an outward-facing conformation is stabilized by the outerlock formed by residues K120 and E351, which allows LPL access to the periplasmic binding site; ii) substrate binding induces a protein conformational change to open the innerlock to form an occluded state, allowing the substrate to pass via the shuttle site in the middle of the membrane towards the cytoplasmic binding site; iii) an inward-opening state is induced by outerlock formation of residues D30 and R236, which allows the substrate to be released from the cytoplasmic site to the inner leaflet of the membrane.

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