The Vps13 Family of Lipid Transporters and Its Role at Membrane Contact Sites

Abstract

The conserved VPS13 proteins constitute a new family of lipid transporters at membrane contact sites. These large proteins are suspected to bridge membranes and form a direct channel for lipid transport between organelles. Mutations in the 4 human homologs (VPS13A-D) are associated with a number of neurological disorders, but little is known about their precise functions or the relevant contact sites affected in disease. In contrast, yeast has a single Vps13 protein which is recruited to multiple organelles and contact sites. The yeast model system has proved useful for studying the function of Vps13 at different organelles and identifying the localization determinants responsible for its membrane targeting. In this review we describe recent advances in our understanding of VPS13 proteins with a focus on yeast research.

Keywords: Atg2; Cohen syndrome; Parkinson’s disease; Vps13; ataxia; chorea acanthocytosis; lipid transport; membrane contact sites; yeast model.

Figure 1

Domain architecture of VPS13 and ATG2 proteins. (A) Ribbon models of the crystal structure of residues 1-325 of C. thermophilum Vps13 lacking residues 95-132 (Protein Data Bank accession No. 6CBC) [15]. Residues are coloured blue to red from 1 to 325. (B) Cryo-EM structure of residues 1-1390 of C. thermophilum Vps13 (EMD-21113, 3.75 Å resolution) [37]. (C) Shared conserved domains of S. cerevisiae and human VPS13 and ATG2 proteins drawn approximately to scale. Domains occurring in individual proteins, such as the ubiquitin-associated (UBA) domain of VPS13D, are not shown. Domains and abbreviations are as follows: Chorein domain; VAB, Vps13 Adaptor Binding/WD40 domain; APT1 domain; ATG2_C, Autophagy-related protein 2 C-terminal domain; and PH, Pleckstrin homology domain. The region of yeast Vps13 corresponding to the cryo-EM structure of C. thermophilum Vps13 [37] is shown in pale blue.

Figure 2

Model of Vps13 membrane targeting determinants. The Vps13 lipid transport channel bridges organelle membranes at contact sites through membrane targeting determinants on either end. An N-terminal helix in the chorein domain is predicted to target membranes. Within the C-terminus, the six-repeat Vps13 Adaptor Binding (VAB) domain binds proline-X-proline (PxP) motif-containing adaptors at a site within repeats 5–6. Additional C-terminal conserved APT1, Autophagy-related protein 2 C-terminal (ATG2_C) and Pleckstrin homology (PH) domains have putative membrane targeting roles that may function cooperatively to position the lipid transport channel. Arrows indicate the presumed direction of lipid transport along a hydrophobic groove shown by dotted lines. The N- and C-termini of Vps13 are indicated. Model not to scale.

Figure 3

Proposed mechanism of VPS13 lipid transport at membrane contact sites. Unidirectional transport of bulk lipids by VPS13 proteins may be driven by localized lipid synthesis at donor membranes and scramblase activity on acceptor membranes. Putative lipid synthesis enzymes are shown in teal and green. These enzymes, which may or may not be coupled directly to VPS13 proteins, could provide a source of newly synthesized lipids for bulk transport. A putative scramblase at the acceptor membrane is shown in purple. Scramblases that non-specifically translocate lipids between acceptor membrane leaflets allow membrane expansion to occur. XK, a predicted phospholipid scramblase, has been recently shown to interact with VPS13A [56]. Model not to scale.