A partnership between the lipid scramblase XK and the lipid transfer protein VPS13A at the plasma membrane

Abstract

Chorea-acanthocytosis (ChAc) and McLeod syndrome are diseases with shared clinical manifestations caused by mutations in VPS13A and XK, respectively. Key features of these conditions are the degeneration of caudate neurons and the presence of abnormally shaped erythrocytes. XK belongs to a family of plasma membrane (PM) lipid scramblases whose action results in exposure of PtdSer at the cell surface. VPS13A is an endoplasmic reticulum (ER)-anchored lipid transfer protein with a putative role in the transport of lipids at contacts of the ER with other membranes. Recently VPS13A and XK were reported to interact by still unknown mechanisms. So far, however, there is no evidence for a colocalization of the two proteins at contacts of the ER with the PM, where XK resides, as VPS13A was shown to be localized at contacts between the ER and either mitochondria or lipid droplets. Here we show that VPS13A can also localize at ER–PM contacts via the binding of its PH domain to a cytosolic loop of XK, that such interaction is regulated by an intramolecular interaction within XK, and that both VPS13A and XK are highly expressed in the caudate neurons. Binding of the PH domain of VPS13A to XK is competitive with its binding to intracellular membranes that mediate other tethering functions of VPS13A. Our findings support a model according to which VPS13A-dependent lipid transfer between the ER and the PM is coupled to lipid scrambling within the PM. They raise the possibility that defective cell surface exposure of PtdSer may be responsible for neurodegeneration.

Sequence Analysis and Structural Predictions of Lipid Transfer Bridges in the Repeating Beta Groove (RBG) Superfamily Reveal Past and Present Domain Variations Affecting Form, Function and Interactions of VPS13, ATG2, SHIP164, Hobbit and Tweek

“…Thus, ColabFold predicts that the rod-like molecule VPS13 forms a single continuous β-groove from end to end, resembling other members of the superfamily (Figure 2D). This matches cryo-EM observations of VPS13 as a rod (De et al, 2017) with a groove along at least part of its length (Li et al, 2020), and has been reported elsewhere (Adlakha et al, 2022; Guillén-Samander et al, 2022). This finding indicates that the VAB repeats, six all-beta domains of a unique type that build into a curved structure shaped like a hook (Bean et al, 2018; Adlakha et al, 2022), can be considered as a VPS13-specific insert in the loop between RBG domains (RBG10 and 11, see Figure 1A).…”

“…Analysis of the predicted structures of these proteins identified a repeating unit consisting of a 5-stranded β-sheet meander plus a sixth element, which usually starts with a helix and then continues with a loop that crosses back over the meander (Figure 1B) (Neuman et al, 2022b). The rods are superhelical, which makes it hard to see the details of their construction (Guillén-Samander et al, 2022; Toulmay et al, 2022). There are some portions of predicted structure where the superhelical twist is low, and here the core building block is easily seen (Figure 1C).…”

Parallel phospholipid transfer by Vps13 and Atg2 determines autophagosome biogenesis dynamics

“…In this context, it remains to be analyzed whether Vps13 binds to a dedicated scramblase or relies directly or indirectly on Atg9-mediated scrambling within the phagophore membrane. Recent work has identified that yeast Vps13 and human VPS13A are coupled with the scramblases Mcp1 in mitochondria and XK in the plasma membrane, respectively (Adlakha et al, 2022; Guillen-Samander et al, 2022; Park et al, 2022). Human VPS13A-D variants are associated with distinct pathologies (Ugur et al, 2020).…”

A complex containing RhoBTB3-SHIP164-Vps26B promotes the biogenesis of early endosome buds at Golgi-endosome contacts

“…Atg2, proposed to transfer bulk lipids from the ER during autophagosome biogenesis, interacts with two ER-resident scramblases TMEM41B 52,53 and VMP1 53 , and with a Golgi-resident scramblase Atg9, that initiate the foramtion of autophagosome 51 . Vps13A was suggested to interact with a PM-resident scramblase XK [54][55][56][57] . It is tempting to speculate that SHIP164 may also cooperate with scramblases to mediate the lipid transfer from the Golgi to EEs.…”