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Phosphatidylinositol phosphates modulate interactions between the StarD4 sterol trafficking protein and lipid membranes
There is substantial evidence for extensive nonvesicular sterol transport in cells. For example, lipid transfer by the steroidogenic acute regulator-related proteins (StarD) containing a StarT domain has been shown to involve several pathways of nonvesicular trafficking. Among the soluble StarT doma...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Society for Biochemistry and Molecular Biology
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9207681/ https://www.ncbi.nlm.nih.gov/pubmed/35605664 http://dx.doi.org/10.1016/j.jbc.2022.102058 |
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author | Zhang, Xiaoxue Xie, Hengyi Iaea, David Khelashvili, George Weinstein, Harel Maxfield, Frederick R. |
author_facet | Zhang, Xiaoxue Xie, Hengyi Iaea, David Khelashvili, George Weinstein, Harel Maxfield, Frederick R. |
author_sort | Zhang, Xiaoxue |
collection | PubMed |
description | There is substantial evidence for extensive nonvesicular sterol transport in cells. For example, lipid transfer by the steroidogenic acute regulator-related proteins (StarD) containing a StarT domain has been shown to involve several pathways of nonvesicular trafficking. Among the soluble StarT domain–containing proteins, StarD4 is expressed in most tissues and has been shown to be an effective sterol transfer protein. However, it was unclear whether the lipid composition of donor or acceptor membranes played a role in modulating StarD4-mediated transport. Here, we used fluorescence-based assays to demonstrate a phosphatidylinositol phosphate (PIP)-selective mechanism by which StarD4 can preferentially extract sterol from liposome membranes containing certain PIPs (especially, PI(4,5)P(2) and to a lesser degree PI(3,5)P2). Monophosphorylated PIPs and other anionic lipids had a smaller effect on sterol transport. This enhancement of transport was less effective when the same PIPs were present in the acceptor membranes. Furthermore, using molecular dynamics (MD) simulations, we mapped the key interaction sites of StarD4 with PIP-containing membranes and identified residues that are important for this interaction and for accelerated sterol transport activity. We show that StarD4 recognizes membrane-specific PIPs through specific interaction with the geometry of the PIP headgroup as well as the surrounding membrane environment. Finally, we also observed that StarD4 can deform membranes upon longer incubations. Taken together, these results suggest a mechanism by which PIPs modulate cholesterol transfer activity via StarD4. |
format | Online Article Text |
id | pubmed-9207681 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | American Society for Biochemistry and Molecular Biology |
record_format | MEDLINE/PubMed |
spelling | pubmed-92076812022-06-27 Phosphatidylinositol phosphates modulate interactions between the StarD4 sterol trafficking protein and lipid membranes Zhang, Xiaoxue Xie, Hengyi Iaea, David Khelashvili, George Weinstein, Harel Maxfield, Frederick R. J Biol Chem Research Article There is substantial evidence for extensive nonvesicular sterol transport in cells. For example, lipid transfer by the steroidogenic acute regulator-related proteins (StarD) containing a StarT domain has been shown to involve several pathways of nonvesicular trafficking. Among the soluble StarT domain–containing proteins, StarD4 is expressed in most tissues and has been shown to be an effective sterol transfer protein. However, it was unclear whether the lipid composition of donor or acceptor membranes played a role in modulating StarD4-mediated transport. Here, we used fluorescence-based assays to demonstrate a phosphatidylinositol phosphate (PIP)-selective mechanism by which StarD4 can preferentially extract sterol from liposome membranes containing certain PIPs (especially, PI(4,5)P(2) and to a lesser degree PI(3,5)P2). Monophosphorylated PIPs and other anionic lipids had a smaller effect on sterol transport. This enhancement of transport was less effective when the same PIPs were present in the acceptor membranes. Furthermore, using molecular dynamics (MD) simulations, we mapped the key interaction sites of StarD4 with PIP-containing membranes and identified residues that are important for this interaction and for accelerated sterol transport activity. We show that StarD4 recognizes membrane-specific PIPs through specific interaction with the geometry of the PIP headgroup as well as the surrounding membrane environment. Finally, we also observed that StarD4 can deform membranes upon longer incubations. Taken together, these results suggest a mechanism by which PIPs modulate cholesterol transfer activity via StarD4. American Society for Biochemistry and Molecular Biology 2022-05-20 /pmc/articles/PMC9207681/ /pubmed/35605664 http://dx.doi.org/10.1016/j.jbc.2022.102058 Text en © 2022 The Authors https://creativecommons.org/licenses/by/4.0/This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Research Article Zhang, Xiaoxue Xie, Hengyi Iaea, David Khelashvili, George Weinstein, Harel Maxfield, Frederick R. Phosphatidylinositol phosphates modulate interactions between the StarD4 sterol trafficking protein and lipid membranes |
title | Phosphatidylinositol phosphates modulate interactions between the StarD4 sterol trafficking protein and lipid membranes |
title_full | Phosphatidylinositol phosphates modulate interactions between the StarD4 sterol trafficking protein and lipid membranes |
title_fullStr | Phosphatidylinositol phosphates modulate interactions between the StarD4 sterol trafficking protein and lipid membranes |
title_full_unstemmed | Phosphatidylinositol phosphates modulate interactions between the StarD4 sterol trafficking protein and lipid membranes |
title_short | Phosphatidylinositol phosphates modulate interactions between the StarD4 sterol trafficking protein and lipid membranes |
title_sort | phosphatidylinositol phosphates modulate interactions between the stard4 sterol trafficking protein and lipid membranes |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9207681/ https://www.ncbi.nlm.nih.gov/pubmed/35605664 http://dx.doi.org/10.1016/j.jbc.2022.102058 |
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