The Extended-Synaptotagmins

Abstract

The extended-synaptotagmins (tricalbins in yeast) derive their name from their partial domain structure similarity to the synaptotagmins, which are characterized by an N-terminal membrane anchor and cytosolically exposed C2 domains. However, they differ from the synaptotagmins in localization and function. The synaptotagmins tether secretory vesicles, including synaptic vesicles, to the plasma membrane (PM) via their C2 domains and regulate their Ca2+ triggered exocytosis. In contrast, the extended-synaptotagmins are resident proteins of the endoplasmic reticulum (ER), which tether this organelle to the plasma membrane via their C2 domains, but not as a premise to fusion of the two membranes. They transport glycerolipids between the two bilayers via their lipid-harboring SMP domains and Ca2+ regulate their membrane tethering and lipid transport function. Additionally, the extended-synaptotagmins are more widely expressed in different organisms, as they are present not only in animal cells, but also in fungi and plants, which do not express the synaptotagmins. Thus, they have a more general function than the synaptotagmins, whose appearance in animals species correlated with the occurrence of Ca2+ triggered exocytosis.

Ca 2+ releases E‐Syt1 autoinhibition to couple ER ‐plasma membrane tethering with lipid transport

“…All three E-Syts comprise an N-terminal hydrophobic hairpin through which they are anchored to the ER (Giordano et al, 2013;Saheki et al, 2016). This region is followed by a synaptotagmin-like mitochondrial lipid-binding protein (SMP) domain (Lee & Hong, 2006;Kopec et al, 2010;Toulmay & Prinz, 2012;Schauder et al, 2014) and multiple C2 domains, five in E-Syt1 and three in E-Syt2 and E-Syt3 (see Fig 1A; Min et al, 2007;Saheki & De Camilli, 2017b). As shown by the crystal structure, the first two C2 domains of E-Syt2 (C2AB) are arranged in tandem (Schauder et al, 2014;Xu et al, 2014) and a similar arrangement is predicted for the C2AB domains of E-Syt1 and E-Syt3.…”

Functions of Vertebrate Ferlins

“…• Mediate tethering of the ER to the plasma membrane (PM) and lipid transfer (extended synaptotagmins) [27], • Recruit proteins to membranes and are involved in cell signaling (copines and RASAL1) [28][29][30], and, • Phosphorylate inositol phospholipids, thereby influencing intracellular processes like signal transduction or clathrin-mediated endocytosis (PI3KC2s) [31].…”

Tricalbin-Mediated Contact Sites Control ER Curvature to Maintain Plasma Membrane Integrity

“…The tricalbin proteins (Tcb1/2/3) are orthologs of the mammalian extended-synaptotagmins (E-Syts) and the plant synaptotagmins (SYTs) (Pé rez-Sancho et al, 2016;Saheki and De Camilli, 2017b). Tcbs are likely anchored to the ER membrane by a hairpin sequence (Giordano et al, 2013;Saheki and De Camilli, 2017b) (Figure 2A) similar to those found in ER morphogenetic proteins such as reticulons (Hu et al, 2011).…”