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⁺ regulates 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 animal species correlated with the occurrence of Ca²⁺ triggered exocytosis. This article is part of a Special Issue entitled: Membrane Contact Sites edited by Christian Ungermann and Benoit Kornmann.

Keywords: C2; SMP; Synaptotagmin; TULIP; Tricalbin.

Figure 1. E-Syts regulate ER-PM tethering and transport/exchange of lipids

(a) Schematics showing the domain structure of synaptotagmin (Syt1), E-Syts (E-Syt1/2/3) and yeast tricalbins (TCB1/2/3). The amino acid lengths are indicated. (b) (Top) E-Syts, anchored to ER-membrane by a hydrophobic hairpin, form a dimeric complex and mediate ER-PM tethering via their C2 domain-dependent interaction with PM PI(4,5)P₂. This tethering function is additionally regulated by cytosolic Ca²⁺, primarily via the Ca²⁺ sensing properties of the C2C domain of E-Syt1. The SMP dimer mediates lipid transfer likely by shuttling between the ER and the PM. The figure depicts binding of the C2A-C2B pair “in cis” to the ER, where its Ca²⁺ binding properties may help the SMP dimer extract lipids from the ER membrane. However, it cannot be excluded that it may bind “in trans” to the PM. From Saheki and De Camilli. Annual Review of Biochemistry, 2017. (c) Crystal structure of the SMP domain of E-Syt2 with bound hydrophobic molecules (diacyglycerol and Triton-X100 used for the purification of the module) in its hydrophobic groove. The SMP domain forms a dimer (green and blue indicate the two monomer within the dimer). Lipid molecules are shown in red. From Schauder et al. Nature, 2014 [9] (d) Schematics of the potential role of the E-Syts in the control of PM lipid homeostasis in response to PLC activation. E-Syts may cooperate with Nir2 in the transport PI(4,5)P₂ metabolites from the PM to the ER. IP3, inositol 1,4,5-trisphosphate. DAG, diacylglycerol. PA, phosphatidic acid. PLC, phospholipase C. The cytosplasmic leaflet of the PM is depicted in green (rather than in brown as the other membrane leaflets) to indicate the presence of high concentration PI(4,5)P₂ In this membrane.