9.A.57 The Extended-Synaptotagmin (E-Syt) Family
Extended-Synaptotagmin (E-Syt) membrane proteins have been implicated in a range of interrelated cellular functions including calcium and receptor signaling and membrane lipid transport. Their evolutionary conservation and molecular actions have been studied. Herdman and Moss 2016 reviewed E-Syts and discussed their molecular functions and the in vivo requirements for these proteins. Proteins in this family are homologous to synaptotagmins in TC families 1.F.1 and 9.A.48. Synaptotagmin-1 promotes both hemifusion more rapidly than full fusion in a Ca2+-dependent manner (Lu et al. 2006).
Endoplasmic reticulum-plasma membrane (ER-PM) contact sites play a role in cellular processes such as ER-PM assembly which is tethered by the extended synaptotagmins (E-Syt). At steady state, E-Syt2 positions the ER and Sac1, an integral ER membrane lipid phosphatase, in discrete ER-PM junctions (Dickson et al. 2016). Sac1 participates in phosphoinositide homeostasis by limiting PM phosphatidylinositol 4-phosphate (PI(4)P), the precursor of PI(4,5)P2. Activation of G protein-coupled receptors that deplete PM PI(4,5)P2 disrupts E-Syt2-mediated ER-PM junctions, reducing Sac1's access to the PM and permitting PM PI(4)P and PI(4,5)P2 to recover. Conversely, depletion of ER luminal calcium increases the amount of Sac1 in contact with the PM, depleting PM PI(4)P. Thus, the dynamic presence of Sac1 at ER-PM contact sites allows it to act as a cellular sensor and controller of PM phosphoinositides, thereby influencing many PM processes.
Organelles are in constant communication with each other through exchange of proteins (mediated by trafficking vesicles) and lipids [mediated by both trafficking vesicles and lipid transfer proteins (LTPs)]. Vesicle trafficking can be regulated by the second messenger Ca2+, allowing membrane protein transport to be adjusted according to physiological demands. Yu et al. 2016 showed that E-Syts are Ca2+-dependent LTPs. E-Syts transfer glycerophospholipids between membrane bilayers in the presence of Ca2+. They use their lipid-accommodating synaptotagmin-like mitochondrial lipid binding protein (SMP) domains to transfer lipids. However, the SMP domains themselves cannot transport lipids unless the two membranes are tightly tethered by Ca2+-bound C2 domains. The Ca2+-regulated lipid transfer activity of E-Syts is restored when the SMP domain is fused to the cytosolic domain of synaptotagmin-1, the Ca2+sensor in synaptic vesicle fusion, indicating that a common mechanism of membrane tethering governs the Ca2+regulation of lipid transfer and vesicle fusion (see TC family 1.F.1). Microsomal vesicles isolated from mammalian cells contain robust Ca2+-dependent lipid transfer activities, mediated by E-Syts. Thus, E-Syts are a novel class of LTPs (Yu et al. 2016).
The tubular lipid-binding (TULIP) superfamily is a major mediator of lipid sensing and transport in eukaryotes. It encompasses three protein families, SMP-like, BPI-like, and Takeout-like, which share a common fold (Alva and Lupas 2016). This fold consists of a long helix wrapped in a highly curved anti-parallel β-sheet, enclosing a central, lipophilic cavity. The SMP-like proteins, which include subunits of the ERMES complex and the extended synaptotagmins (E-Syts), appear to be mainly located at membrane contacts sites (MCSs) between organelles, mediating inter-organelle lipid exchange. The BPI-like proteins, which include the bactericidal/permeability-increasing protein (BPI), the LPS (lipopolysaccharide)-binding protein (LBP), the cholesteryl ester transfer protein (CETP), and the phospholipid transfer protein (PLTP), are either involved in innate immunity against bacteria through their ability to sense lipopolysaccharides, as is the case for BPI and LBP, or in lipid exchange between lipoprotein particles, as is the case for CETP and PLTP. The Takeout-like proteins, which are comprised of insect juvenile hormone-binding proteins and arthropod allergens, transport lipid hormones to target tissues during insect development. In all cases, the activity of these proteins is underpinned by their ability to bind large, hydrophobic ligands in their central cavity and segregate them away from the aqueous environment. Furthermore, where they are involved in lipid exchange, recent structural studies have highlighted their ability to establish lipophilic, tubular channels, either between organelles in the case of SMP domains or between lipoprotein particles in the case of CETP. Alva and Lupas 2016 reviewed the structures, versatile functions, and evolution of proteins of the TULIP superfamily. They proposed a deep evolutionary split in this superfamily, predating the Last Eukaryotic Common Ancestor, between the SMP-like proteins, which act on lipids endogenous to the cell, and the BPI-like proteins (including the Takeout-like proteins of arthropods), which act on exogenous lipids.