A partnership between the lipid scramblase XK and the lipid transfer protein VPS13A at the plasma membrane
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pnas.2205425119.pdf
Description
Published version
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2.88 MB
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Checksum (MD5)
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Author(s)
Guillén-Samander, Andrés
Wu, Yumei
Pineda, S Sebastian
García, Francisco J
Eisen, Julia N
Leonzino, Marianna
Ugur, Berrak
Kellis, Manolis
Heiman, Myriam
De Camilli, Pietro
Date Issued
2022
Journal
Proceedings of the National Academy of Sciences of the United States of America
Publisher
Proceedings of the National Academy of Sciences
Citation
Guillén-Samander, Andrés, Wu, Yumei, Pineda, S Sebastian, García, Francisco J, Eisen, Julia N et al. 2022. "A partnership between the lipid scramblase XK and the lipid transfer protein VPS13A at the plasma membrane." Proceedings of the National Academy of Sciences of the United States of America, 119 (35).
Version
Final published version
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.
MIT Department
Massachusetts Institute of Technology. Department of Brain and Cognitive Sciences
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Creative Commons Attribution 4.0 International license
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DOI of Published Version
10.1073/PNAS.2205425119
