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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). Synaptotagmin is a calcium sensor that can trigger exocytosis (Kiessling et al. 2018). Thirty 0ne Multiple C2 domains and transmembrane region proteins (MCTPs), which may act as transport mediators of other regulators have been described for Gossypium hirsutum (cotton) (Hao et al. 2020). In humans and other mammals, roles of synaptotagmin family members in cancer have been discussed (Suo et al. 2022).

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. Ca2+ plays a critical role in triggering all three primary modes of neurotransmitter release (synchronous, asynchronous, and spontaneous) (Zhou 2023). Synaptotagmin1, a protein with two C2 domains, is the first isoform of the synaptotagmin family that was identified and shown to be the primary Ca2+ sensor for synchronous neurotransmitter release. Other isoforms of the synaptotagmin family as well as other C2 proteins such as the double C2 domain protein family were found to act as Ca2+ sensors for different modes of neurotransmitter release (Zhou 2023).

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.

References associated with 9.A.57 family:

Alva, V. and A.N. Lupas. (2016). The TULIP superfamily of eukaryotic lipid-binding proteins as a mediator of lipid sensing and transport. Biochim. Biophys. Acta. [Epub: Ahead of Print] 26825693
Chang, C.L., T.S. Hsieh, T.T. Yang, K.G. Rothberg, D.B. Azizoglu, E. Volk, J.C. Liao, and J. Liou. (2013). Feedback regulation of receptor-induced Ca2+ signaling mediated by E-Syt1 and Nir2 at endoplasmic reticulum-plasma membrane junctions. Cell Rep 5: 813-825. 24183667
Guo, T., Z. Duan, J. Chen, C. Xie, Y. Wang, P. Chen, and X. Wang. (2017). Pull-down combined with proteomic strategy reveals functional diversity of synaptotagmin I. PeerJ 5: e2973. 28194317
Hao, P., H. Wang, L. Ma, A. Wu, P. Chen, S. Cheng, H. Wei, and S. Yu. (2020). Genome-wide identification and characterization of multiple C2 domains and transmembrane region proteins in Gossypium hirsutum. BMC Genomics 21: 445. 32600247
Honsbein, A., S. Sokolovski, C. Grefen, P. Campanoni, R. Pratelli, M. Paneque, Z. Chen, I. Johansson, and M.R. Blatt. (2009). A tripartite SNARE-K+ channel complex mediates in channel-dependent K+ nutrition in Arabidopsis. Plant Cell 21: 2859-2877. 19794113
Izumi, T., K. Kasai, and H. Gomi. (2007). Secretory vesicle docking to the plasma membrane: molecular mechanism and functional significance. Diabetes Obes Metab 9Suppl2: 109-117. 17919185
Joshi, A.S., B. Nebenfuehr, V. Choudhary, P. Satpute-Krishnan, T.P. Levine, A. Golden, and W.A. Prinz. (2018). Lipid droplet and peroxisome biogenesis occur at the same ER subdomains. Nat Commun 9: 2940. 30054481
Kiessling, V., A.J.B. Kreutzberger, B. Liang, S.B. Nyenhuis, P. Seelheim, J.D. Castle, D.S. Cafiso, and L.K. Tamm. (2018). A molecular mechanism for calcium-mediated synaptotagmin-triggered exocytosis. Nat Struct Mol Biol 25: 911-917. 30291360
Liu, L., C. Li, S. Song, Z.W.N. Teo, L. Shen, Y. Wang, D. Jackson, and H. Yu. (2018). FTIP-Dependent STM Trafficking Regulates Shoot Meristem Development in Arabidopsis. Cell Rep 23: 1879-1890. 29742441
Lu, X., Y. Xu, F. Zhang, and Y.K. Shin. (2006). Synaptotagmin I and Ca2+ promote half fusion more than full fusion in SNARE-mediated bilayer fusion. FEBS Lett. 580: 2238-2246. 16566927
Rafi, S.K., A. Fernández-Jaén, S. Álvarez, O.W. Nadeau, and M.G. Butler. (2019). High Functioning Autism with Missense Mutations in Synaptotagmin-Like Protein 4 (SYTL4) and Transmembrane Protein 187 (TMEM187) Genes: SYTL4- Protein Modeling, Protein-Protein Interaction, Expression Profiling and MicroRNA Studies. Int J Mol Sci 20:. 31323913
Song, S., Y. Chen, L. Liu, Y. Wang, S. Bao, X. Zhou, Z.W. Teo, C. Mao, Y. Gan, and H. Yu. (2017). OsFTIP1-Mediated Regulation of Florigen Transport in Rice Is Negatively Regulated by a Ubiquitin-like Domain Kinase OsUbDKγ4. Plant Cell. [Epub: Ahead of Print] 28254780
Suo, H., N. Xiao, and K. Wang. (2022). Potential roles of synaptotagmin family members in cancers: Recent advances and prospects. Front Med (Lausanne) 9: 968081. 36004367
Yu, H., Y. Liu, D.R. Gulbranson, A. Paine, S.S. Rathore, and J. Shen. (2016). Extended synaptotagmins are Ca2+-dependent lipid transfer proteins at membrane contact sites. Proc. Natl. Acad. Sci. USA. [Epub: Ahead of Print] 27044075
Zhou, Q. (2023). Calcium Sensors of Neurotransmitter Release. Adv Neurobiol 33: 119-138. 37615865