A partnership between the lipid scramblase XK and the lipid transfer protein VPS13A at the plasma membrane
<jats:p>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...
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| Format: | Article |
| Language: | English |
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Proceedings of the National Academy of Sciences
2023
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| Online Access: | https://hdl.handle.net/1721.1/148820 |
| _version_ | 1811072411610644480 |
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| author | 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 |
| author2 | Massachusetts Institute of Technology. Department of Brain and Cognitive Sciences |
| author_facet | Massachusetts Institute of Technology. Department of Brain and Cognitive Sciences 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 |
| author_sort | Guillén-Samander, Andrés |
| collection | MIT |
| description | <jats:p>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.</jats:p> |
| first_indexed | 2024-09-23T09:05:37Z |
| format | Article |
| id | mit-1721.1/148820 |
| institution | Massachusetts Institute of Technology |
| language | English |
| last_indexed | 2024-09-23T09:05:37Z |
| publishDate | 2023 |
| publisher | Proceedings of the National Academy of Sciences |
| record_format | dspace |
| spelling | mit-1721.1/1488202023-03-29T03:47:48Z A partnership between the lipid scramblase XK and the lipid transfer protein VPS13A at the plasma membrane 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 Massachusetts Institute of Technology. Department of Brain and Cognitive Sciences <jats:p>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.</jats:p> 2023-03-28T16:38:23Z 2023-03-28T16:38:23Z 2022 2023-03-28T16:18:17Z Article http://purl.org/eprint/type/JournalArticle https://hdl.handle.net/1721.1/148820 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). en 10.1073/PNAS.2205425119 Proceedings of the National Academy of Sciences of the United States of America Creative Commons Attribution 4.0 International license https://creativecommons.org/licenses/by/4.0/ application/pdf Proceedings of the National Academy of Sciences PNAS |
| spellingShingle | 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 A partnership between the lipid scramblase XK and the lipid transfer protein VPS13A at the plasma membrane |
| title | A partnership between the lipid scramblase XK and the lipid transfer protein VPS13A at the plasma membrane |
| title_full | A partnership between the lipid scramblase XK and the lipid transfer protein VPS13A at the plasma membrane |
| title_fullStr | A partnership between the lipid scramblase XK and the lipid transfer protein VPS13A at the plasma membrane |
| title_full_unstemmed | A partnership between the lipid scramblase XK and the lipid transfer protein VPS13A at the plasma membrane |
| title_short | A partnership between the lipid scramblase XK and the lipid transfer protein VPS13A at the plasma membrane |
| title_sort | partnership between the lipid scramblase xk and the lipid transfer protein vps13a at the plasma membrane |
| url | https://hdl.handle.net/1721.1/148820 |
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