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

Chorea-acanthocytosis 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 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.

1. 1
   Highly accurate protein structure prediction with AlphaFold

   Nature202143,672 citationsDataRank 1.6
2. 2
   AlphaFold Protein Structure Database: massively expanding the structural coverage of protein-sequence space with high-accuracy models

   Nucleic Acids Research20218,161 citationsDataRank 14.9Top 13%
3. 3
   Cell Type-Specific Transcriptomics Reveals that Mutant Huntingtin Leads to Mitochondrial RNA Release and Neuronal Innate Immune Activation

   Neuron2020290 citationsDataRank 0.851
4. 4
   A partnership between the lipid scramblase XK and the lipid transfer protein VPS13A at the plasma membrane

   Proceedings of the National Academy of Sciences202274 citationsDataRank 2.2