Abstract
Eukaryotic cells are characterized by their exquisite compartmentalization resulting from a cornucopia of membrane-bound organelles. Each of these compartments hosts a flurry of biochemical reactions and supports biological functions such as genome storage, membrane protein and lipid biosynthesis/degradation and ATP synthesis, all essential to cellular life. Acting as hubs for the transfer of matter and signals between organelles and throughout the cell, membrane contacts sites (MCSs), sites of close apposition between membranes from different organelles, are essential to cellular homeostasis. One of the now well-acknowledged function of MCSs involves the non-vesicular trafficking of lipids; its characterization answered one long-standing question of eukaryotic cell biology revealing how some organelles receive and distribute their membrane lipids in absence of vesicular trafficking. The endoplasmic reticulum (ER) in synergy with the mitochondria, stands as the nexus for the biosynthesis and distribution of phospholipids (PLs) throughout the cell by contacting nearly all other organelle types. MCSs create and maintain lipid fluxes and gradients essential to the functional asymmetry and polarity of biological membranes throughout the cell. Membrane apposition is mediated by proteinaceous tethers some of which function as lipid transfer proteins (LTPs). We summarize here the current state of mechanistic knowledge of some of the major classes of LTPs and tethers based on the available atomic to near-atomic resolution structures of several “model” MCSs from yeast but also in Metazoans; we describe different models of lipid transfer at MCSs and analyze the determinants of their specificity and directionality. Each of these systems illustrate fundamental principles and mechanisms for the non-vesicular exchange of lipids between eukaryotic membrane-bound organelles essential to a wide range of cellular processes such as at PL biosynthesis and distribution, lipid storage, autophagy and organelle biogenesis.
Highlights
Cellular compartments are present in both prokaryotic and eukaryotic cells; their compositions though are fundamentally different
The endoplasmic reticulum (ER) is the main site of PL biosynthesis and central supplier to the rest of the cell, while mitochondria use a considerable amount of PLs for their membrane biogenesis; the PL biosynthetic pathway in eukaryotes in general and in yeast in particular share a remarkable feature (Horvath and Daum, 2013; Tamura et al, 2014; Tatsuta et al, 2014; Tamura and Endo, 2017; Acoba et al, 2020) where the ER and mitochondria depend on each other for the exchange of intermediates necessary to its completion (Figure 2)
lipid transfer proteins (LTPs) constitute a large and structurally diverse functional class of proteins (Wong et al, 2017; Wong et al, 2019), encompassing members from several proteinfamilies with their associated lipid-binding protein fold such as the Steroidogenic Acute Regulatory-lipid related Transfer (StART) proteins and their StART-like relatives (StARkin) (Alpy and Tomasetto, 2014; Wong and Levine, 2016; Horenkamp et al, 2018; Jentsch et al, 2018) or the Tubular Lipid-binding domain superfamily (TULIP) (Alva and Lupas, 2016; Wong and Levine, 2017) that includes the subgroup of Synaptotagmin-like Mitochondrial lipid-binding Protein domain (SMP) (Lee and Hong, 2006) exclusively associated with membrane contacts sites (MCSs) (Toulmay and Prinz, 2012) (Figure 3)
Summary
Cellular compartments are present in both prokaryotic and eukaryotic cells; their compositions though are fundamentally different. The ER is the main site of PL biosynthesis and central supplier to the rest of the cell, while mitochondria use a considerable amount of PLs for their membrane biogenesis; the PL biosynthetic pathway in eukaryotes in general and in yeast in particular share a remarkable feature (Horvath and Daum, 2013; Tamura et al, 2014; Tatsuta et al, 2014; Tamura and Endo, 2017; Acoba et al, 2020) where the ER and mitochondria depend on each other for FIGURE 3 | Structural gallery of protein folds and domains observed in lipid-transfer proteins. The structures described have all been deposited at the Protein Data Bank (www.rcsb.org) and the Unified Data Resource for 3D-EM (www.emdataresource.org) and are referenced with their identifiers throughout this review
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