SMP domain proteins in membrane lipid dynamics
Introduction
The endoplasmic reticulum (ER) spreads throughout the cell and forms physical contacts with virtually all other cellular organelles and the plasma membrane (PM) [1,2]. At these contacts (i.e. membrane contact sites), protein-protein and/or protein-lipid interactions mediate tethering of two closely apposed membranes (typically 10–30 nm) without inducing membrane fusion. Recent studies have identified a number of key proteins, including SMP domain proteins, that localize to these membrane contact sites and regulate their tethering and functions, such as lipid transport, organelle dynamics, Ca2+ homeostasis and signaling [[3], [4], [5], [6], [7], [8], [9], [10]].
SMP domain proteins belong to the superfamily of TUbular LIPid-binding (TULIP) domain-containing proteins, which additionally contain the bacterial/permeability-increasing protein-like (BPI-like) family proteins and Takeout-like family proteins [11]. BPI-like and Takeout-like family proteins are extracellular proteins with various functions, ranging from immunity against bacteria to lipid transport between lipoproteins [11]. In contrast, SMP domain proteins are intracellular proteins, localizing at various membrane contact sites [12].
TULIP domains adopt cylindrical barrel-like structure with a central cavity lined with hydrophobic amino acid residues that binds to lipids and other hydrophobic ligands [11]. Indeed, structural studies revealed that the SMP domain accommodates acyl chains of glycerolipids through its central hydrophobic cavity with or without particular selectivity against their headgroup (see the sections below for the lipid binding preference of individual SMP domains) [[13], [14], [15], [16], [17]]. As SMP domain proteins localize to membrane contact sites, they are proposed to play major roles in transporting lipids between the ER and other organelles or the PM. Studies of SMP domain proteins in several organisms, in particular yeast and mammals, have contributed significantly to our understanding of the mechanisms of intracellular non-vesicular lipid transport. Here, we discuss the functions of SMP domain proteins and summarize their known roles in cell physiology.
Section snippets
E-Syts
Extended-synaptotagmins (E-Syts: E-Syt1, E-Syt2 and E-Syt3) (tricalbins in yeast) are evolutionarily conserved ER-PM tethering proteins that are present in all eukaryotes [[18], [19], [20], [21], [22]] (Fig. 1).
E-Syts, anchored to ER membrane via their N-terminal hydrophobic stretch, possess a cytosolic lipid-harboring SMP domain followed by several C2 domains [18,23] (Fig. 1). They form homo- and hetero-meric complexes and mediate ER-PM tethering via their C2 domain-dependent interaction with
Yeast ERMES complex
Endoplasmic reticulum (ER)-mitochondria encounter structure (ERMES) consists of three SMP domain proteins (Mmm1, Mdm34 and Mdm12), Mdm10, and accessory proteins, including Gem1 and Tom7 [[43], [44], [45], [46], [47]] (Fig. 1). ERMES components were identified through a screen for yeast mutants that could not grow well without an artificial synthetic ER-mitochondria tethering protein; disruption of a single ERMES component leads to disassembly of the entire complex [48].
Mmm1 is integral to ER
Nvj2/TEX2
Yeast Nvj2 (TEX2/HT008 in mammals) has a N-terminal transmembrane domain followed by a PH domain and a SMP domain, and primarily localizes to the NVJ [12] (Fig. 1). Furthermore, quantitative proteomics analysis of yeast proteins identified Nvj2 as a protein enriched in tubular ER [74]. When NVJ formation is disrupted (as in the case of cells lacking Nvj1) or ER function is compromised due to ER stress, Nvj2 moves to ER-Golgi contacts [75]. The localization of Nvj2 to ER-Golgi contacts depend on
Open questions
Growing evidence has demonstrated the critical roles of SMP domain proteins in cell physiology. With the combination of various experimental approaches, including high-resolution imaging and genetic/molecular manipulations, the localization dynamics of SMP domain proteins and how they tether the ER and other organelles and the PM are becoming clear. Furthermore, biochemical and structural studies have contributed significantly to our knowledge of SMP domain-dependent lipid transport/exchange.
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Acknowledgements
We apologize to all the investigators whose work could not be cited due to space limitations. We thank Bilge Ercan for her help in the visualization of the structures of the SMP domains and Jingbo Sun, Nur Raihanah Binte Mohd Harion, Tomoki Naito, and Dylan Hong Zheng Koh for their constructive feedback to the manuscript. Work from the authors related to this review has been supported in part by a Grant-in-Aid for Young Scientists (A) from the Japan Society for the Promotion of Science (17H05065
Conflict of interests
The authors declare no competing interests.
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Reconstitution and biochemical studies of extended synaptotagmin-mediated lipid transport
2022, Methods in EnzymologyCitation Excerpt :Most LTPs span the membranes when they locate at MCSs, contributing to the maintenance of MCS architectures, which brings difficulties in examining their lipid transfer function in the cellular assays. Extended synaptotagmins (E-Syts) belong to the synaptotagmin-like mitochondrial lipid-binding protein (SMP) domain protein family (Creutz, Snyder, & Schulz, 2004; Jeyasimman & Saheki, 2020; Lee & Hong, 2006; Min, Chang, & Südhof, 2007). They are integral membrane proteins anchored to the ER membrane through the N-terminal hydrophobic domain, followed by an SMP domain and multiple C2 domains (Lee & Hong, 2006; Manford, Stefan, Yuan, Macgurn, & Emr, 2012; Yu et al., 2016).
Non-vesicular glycerolipids transport in plant cells
2022, Advances in Botanical ResearchCitation Excerpt :C2 domains are able to bind PIPs-enriched PM in a Ca2 +-dependent manner, allowing the localization of E-Syts at ER-PM MCSs (Fig. 2D). At this junction, E-Syts play a dual role as tethers and lipid transporters (Jeyasimman & Saheki, 2020; Saheki et al., 2016). Whereas yeast and human genomes contain three E-Syt genes (Reinisch & De Camilli, 2016), this family is expanded in plants, with seven members found in A. thaliana genome (Table 2) (Ishikawa et al., 2020).
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2021, Cell ReportsCitation Excerpt :These membrane contact sites (MCSs) play essential roles in diverse cellular processes, including lipid metabolism, ion homeostasis, and interorganellar trafficking of biomolecules (Scorrano et al., 2019; Tamura et al., 2019). Although the yeast Saccharomyces cerevisiae has led the way to provide fundamental molecular concepts of organellar tethering, information on the function and the molecular architecture of MCSs in metazoans is accumulating (Elbaz and Schuldiner, 2011; Hönscher and Ungermann, 2014; Jeyasimman and Saheki, 2020; Kohler et al., 2020; Olkkonen, 2015; Prinz, 2014; Tamura et al., 2019; Tong et al., 2019). Conceptually, MCSs are built by an intricate array of interacting tether proteins that connect two opposing membranes and are dynamically regulated in response to changing metabolic regimes (Scorrano et al., 2019).
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