SMP domain proteins in membrane lipid dynamics

https://doi.org/10.1016/j.bbalip.2019.04.007Get rights and content

Highlights

  • SMP domain proteins localize to various membrane contact sites.

  • They tether the ER to the plasma membrane or other organelles.

  • They mediate lipid exchange at membrane contact sites via SMP domains.

  • Some of their functions can be bypassed by other membrane contact sites or proteins.

  • They are expressed by all eukaryotes.

Abstract

Synaptotagmin-like mitochondrial-lipid-binding (SMP) domain proteins are evolutionarily conserved family of proteins in eukaryotes that localize between the endoplasmic reticulum (ER) and either the plasma membrane (PM) or other organelles. They are involved in tethering of these membrane contact sites through interaction with other proteins and membrane lipids. Recent structural and biochemical studies have demonstrated that SMP domain proteins transport a wide variety of lipid species by the ability of the SMP domain to harbor lipids through its unique hydrophobic cavity. Growing evidence suggests that SMP domain proteins play critical roles in cell physiology by their actions at membrane contact sites. In this review, we summarize the functions of SMP domain proteins and their direct roles in lipid transport across different membrane compartments. We also discuss their physiological functions in organisms as well as “bypass” pathways that act in parallel with SMP domain proteins at membrane contact sites.

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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