Abstract
The occurrence of protein mediated lipid transfer between intracellular membranes has been known since the late 1960's. Since these early discoveries, numerous proteins responsible for such transport, which often act at membrane contact sites, have been identified. Typically, they comprise a lipid harboring module thought to shuttle back and forth between the two adjacent bilayers. Recently, however, studies of the chorein domain protein family, which includes VPS13 and ATG2, has led to the identification of a novel mechanism of lipid transport between organelles in eukaryotic cells mediated by a rod-like protein bridge with a hydrophobic groove through which lipids can slide. This mechanism is ideally suited for bulk transport of bilayer lipids to promote membrane growth. Here we describe how studies of VPS13 led to the discovery of this new mechanism, summarize properties and known roles of VPS13 proteins, and discuss how their dysfunction may lead to disease.
Highlights
The function of eukaryotic cells is critically dependent on its compartmentalization by intracellular lipid-based membranes which have distinct lipid composition
As the backbone of most membrane lipids is synthesized in the endoplasmic reticulum (ER), and membrane lipids cannot diffuse through the aqueous environment of the cytosol, cells have evolved two major transport mechanisms to ensure the delivery of lipids to appropriate target membranes and to maintain their specific lipid composition: vesicle-based and protein-mediated lipid transport [1,2,3]
The characterization of the VPS13 protein family and of the related protein ATG2 has introduced a new concept in cell biology: the net flow of bilayer lipids between membranes through molecular pipelines independent of classic vesicular transport
Summary
The function of eukaryotic cells is critically dependent on its compartmentalization by intracellular lipid-based membranes which have distinct lipid composition. As the backbone of most membrane lipids is synthesized in the endoplasmic reticulum (ER), and membrane lipids cannot diffuse through the aqueous environment of the cytosol, cells have evolved two major transport mechanisms to ensure the delivery of lipids to appropriate target membranes and to maintain their specific lipid composition: vesicle-based and protein-mediated lipid transport [1,2,3]. Protein-mediated lipid transport is crucial to circumvent these limitations and ensures the precise tuning of lipid composition in all membrane compartments. Often these lipid transport proteins act at sites of close apposition between two membranes, so called membrane contact sites, where they may function as membrane tethers [8]. We will focus on the properties and putative functions of the founding members of this class of lipid transport proteins, the VPS13 protein family, and on mechanisms of disease resulting from their mutations
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