Abstract
The plasma membrane of neurons consists of distinct domains, each of which carries specialized functions and a characteristic set of membrane proteins. While this compartmentalized membrane organization is essential for neuronal functions, it remains controversial how neurons establish these domains on the laterally fluid membrane. Here, using immunostaining, lipid-MS analysis and gene ablation with the CRISPR/Cas9 system, we report that the pancreatic lipase-related protein 2 (PLRP2), a phospholipase A1 (PLA1), is a key organizer of membrane protein localization at the neurite tips of PC12 cells. PLRP2 produced local distribution of 1-oleoyl-2-palmitoyl-PC at these sites through acyl-chain remodeling of membrane phospholipids. The resulting lipid domain assembled the syntaxin 4 (Stx4) protein within itself by selectively interacting with the transmembrane domain of Stx4. The localized Stx4, in turn, facilitated the fusion of transport vesicles that contained the dopamine transporter with the domain of the plasma membrane, which led to the localized distribution of the transporter to that domain. These results revealed the pivotal roles of PLA1, specifically PLRP2, in the formation of functional domains in the plasma membrane of neurons. In addition, our results suggest a mode of membrane organization in which the local acyl-chain remodeling of membrane phospholipids controls the selective localization of membrane proteins by regulating both lipid-protein interactions and the fusion of transport vesicles to the lipid domain.
Highlights
Supplementary key words glycerophospholipids membrane lipids membranes/fluidity phospholipases phospholipid remodeling acyl-chain configuration phospholipase A1 dopamine transporter syntaxin pancreatic lipase-related protein 2
From the pancreatic lipase-related protein 2 (PLRP2)-deficient cells, neither PLRP2 nor dopamine transporter (DAT) was recovered in the bound fraction (Fig. 6). These results showed that PLRP2, syntaxin 4 (Stx4), and DAT reside in the same transport vesicles and that PLRP2 is necessary for assembling these three cargo proteins on the transport vesicles
Lipid Res. (2020) 61(12) 1747–1763. These results indicated that the transmembrane domain (TMD) of syntaxin 1A (Stx1A) and that of Stx4 are the determinants of their lateral positioning at the plasma membrane, and that the localization of Stx4 at the tips of neurites is dependent on the sequence-specific interaction of its TMD with the characteristic acyl chain configuration of OPPC
Summary
Neurons are one notable example of such cells, as they carry specialized domains at the presynaptic, postsynaptic, and soma membranes, as well as at different regions of the axon This compartmentalized membrane organization is essential for the neuronal transmission of information directionally and for the formation of elaborate neural circuits in the brain. In addition to variation in their hydrophilic portion, phospholipids comprise various molecular species with different combinations of acyl chains, which constitute the hydrophobic core of the lipid bilayer [7, 8] This acyl chain variety is produced by a process called “acyl chain remodeling” or “Lands cycle” [9].
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