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Dynamics and energetics of the mammalian phosphatidylinositol transfer protein phospholipid exchange cycle

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Dynamics and energetics of the mammalian phosphatidylinositol transfer protein phospholipid exchange cycle. / Grabon, Aby; Orłowski, Adam; Tripathi, Ashutosh; Vuorio, Joni; Javanainen, Matti; Róg, Tomasz; Lönnfors, Max; McDermott, Mark I.; Siebert, Garland; Somerharju, Pentti; Vattulainen, Ilpo; Bankaitis, Vytas A.

In: Journal of Biological Chemistry, Vol. 292, No. 35, 2017, p. 14438-14455.

Research output: Contribution to journalArticleScientificpeer-review

Harvard

Grabon, A, Orłowski, A, Tripathi, A, Vuorio, J, Javanainen, M, Róg, T, Lönnfors, M, McDermott, MI, Siebert, G, Somerharju, P, Vattulainen, I & Bankaitis, VA 2017, 'Dynamics and energetics of the mammalian phosphatidylinositol transfer protein phospholipid exchange cycle', Journal of Biological Chemistry, vol. 292, no. 35, pp. 14438-14455. https://doi.org/10.1074/jbc.M117.791467

APA

Grabon, A., Orłowski, A., Tripathi, A., Vuorio, J., Javanainen, M., Róg, T., ... Bankaitis, V. A. (2017). Dynamics and energetics of the mammalian phosphatidylinositol transfer protein phospholipid exchange cycle. Journal of Biological Chemistry, 292(35), 14438-14455. https://doi.org/10.1074/jbc.M117.791467

Vancouver

Grabon A, Orłowski A, Tripathi A, Vuorio J, Javanainen M, Róg T et al. Dynamics and energetics of the mammalian phosphatidylinositol transfer protein phospholipid exchange cycle. Journal of Biological Chemistry. 2017;292(35):14438-14455. https://doi.org/10.1074/jbc.M117.791467

Author

Grabon, Aby ; Orłowski, Adam ; Tripathi, Ashutosh ; Vuorio, Joni ; Javanainen, Matti ; Róg, Tomasz ; Lönnfors, Max ; McDermott, Mark I. ; Siebert, Garland ; Somerharju, Pentti ; Vattulainen, Ilpo ; Bankaitis, Vytas A. / Dynamics and energetics of the mammalian phosphatidylinositol transfer protein phospholipid exchange cycle. In: Journal of Biological Chemistry. 2017 ; Vol. 292, No. 35. pp. 14438-14455.

Bibtex - Download

@article{0eec6235804e47a484f1830415f9a1b8,
title = "Dynamics and energetics of the mammalian phosphatidylinositol transfer protein phospholipid exchange cycle",
abstract = "Phosphatidylinositol-transfer proteins (PITPs) regulate phosphoinositide signaling in eukaryotic cells. The defining feature of PITPs is their ability to exchange phosphatidylinositol (PtdIns) molecules between membranes, and this property is central to PITP-mediated regulation of lipid signaling. However, the details of the PITP-mediated lipid exchange cycle remain entirely obscure. Here, all-atom molecular dynamics simulations of the mammalian StART-like PtdIns/phosphatidylcholine (PtdCho) transfer protein PITP, both on membrane bilayers and in solvated systems, informed downstream biochemical analyses that tested key aspects of the hypotheses generated by the molecular dynamics simulations. These studies provided five key insights into the PITP lipid exchange cycle: (i) interaction of PITP with the membrane is spontaneous and mediated by four specific protein substructures; (ii) the ability of PITP to initiate closure around the PtdCho ligand is accompanied by loss of flexibility of two helix/loop regions, as well as of the C-terminal helix; (iii) the energy barrier of phospholipid extraction from the membrane is lowered by a network of hydrogen bonds between the lipid molecule and PITP; (iv) the trajectory of PtdIns or PtdCho into and through the lipid-binding pocket is chaperoned by sets of PITP residues conserved throughout the StART-like PITP family; and (v) conformational transitions in the C-terminal helix have specific functional involvements in PtdIns transfer activity. Taken together, these findings provide the first mechanistic description of key aspects of the PITP PtdIns/PtdCho exchange cycle and offer a rationale for the high conservation of particular sets of residues across evolutionarily distant members of the meta-zoan StART-like PITP family.",
author = "Aby Grabon and Adam Orłowski and Ashutosh Tripathi and Joni Vuorio and Matti Javanainen and Tomasz R{\'o}g and Max L{\"o}nnfors and McDermott, {Mark I.} and Garland Siebert and Pentti Somerharju and Ilpo Vattulainen and Bankaitis, {Vytas A.}",
year = "2017",
doi = "10.1074/jbc.M117.791467",
language = "English",
volume = "292",
pages = "14438--14455",
journal = "Journal of Biological Chemistry",
issn = "0021-9258",
publisher = "American Society for Biochemistry and Molecular Biology",
number = "35",

}

RIS (suitable for import to EndNote) - Download

TY - JOUR

T1 - Dynamics and energetics of the mammalian phosphatidylinositol transfer protein phospholipid exchange cycle

AU - Grabon, Aby

AU - Orłowski, Adam

AU - Tripathi, Ashutosh

AU - Vuorio, Joni

AU - Javanainen, Matti

AU - Róg, Tomasz

AU - Lönnfors, Max

AU - McDermott, Mark I.

AU - Siebert, Garland

AU - Somerharju, Pentti

AU - Vattulainen, Ilpo

AU - Bankaitis, Vytas A.

PY - 2017

Y1 - 2017

N2 - Phosphatidylinositol-transfer proteins (PITPs) regulate phosphoinositide signaling in eukaryotic cells. The defining feature of PITPs is their ability to exchange phosphatidylinositol (PtdIns) molecules between membranes, and this property is central to PITP-mediated regulation of lipid signaling. However, the details of the PITP-mediated lipid exchange cycle remain entirely obscure. Here, all-atom molecular dynamics simulations of the mammalian StART-like PtdIns/phosphatidylcholine (PtdCho) transfer protein PITP, both on membrane bilayers and in solvated systems, informed downstream biochemical analyses that tested key aspects of the hypotheses generated by the molecular dynamics simulations. These studies provided five key insights into the PITP lipid exchange cycle: (i) interaction of PITP with the membrane is spontaneous and mediated by four specific protein substructures; (ii) the ability of PITP to initiate closure around the PtdCho ligand is accompanied by loss of flexibility of two helix/loop regions, as well as of the C-terminal helix; (iii) the energy barrier of phospholipid extraction from the membrane is lowered by a network of hydrogen bonds between the lipid molecule and PITP; (iv) the trajectory of PtdIns or PtdCho into and through the lipid-binding pocket is chaperoned by sets of PITP residues conserved throughout the StART-like PITP family; and (v) conformational transitions in the C-terminal helix have specific functional involvements in PtdIns transfer activity. Taken together, these findings provide the first mechanistic description of key aspects of the PITP PtdIns/PtdCho exchange cycle and offer a rationale for the high conservation of particular sets of residues across evolutionarily distant members of the meta-zoan StART-like PITP family.

AB - Phosphatidylinositol-transfer proteins (PITPs) regulate phosphoinositide signaling in eukaryotic cells. The defining feature of PITPs is their ability to exchange phosphatidylinositol (PtdIns) molecules between membranes, and this property is central to PITP-mediated regulation of lipid signaling. However, the details of the PITP-mediated lipid exchange cycle remain entirely obscure. Here, all-atom molecular dynamics simulations of the mammalian StART-like PtdIns/phosphatidylcholine (PtdCho) transfer protein PITP, both on membrane bilayers and in solvated systems, informed downstream biochemical analyses that tested key aspects of the hypotheses generated by the molecular dynamics simulations. These studies provided five key insights into the PITP lipid exchange cycle: (i) interaction of PITP with the membrane is spontaneous and mediated by four specific protein substructures; (ii) the ability of PITP to initiate closure around the PtdCho ligand is accompanied by loss of flexibility of two helix/loop regions, as well as of the C-terminal helix; (iii) the energy barrier of phospholipid extraction from the membrane is lowered by a network of hydrogen bonds between the lipid molecule and PITP; (iv) the trajectory of PtdIns or PtdCho into and through the lipid-binding pocket is chaperoned by sets of PITP residues conserved throughout the StART-like PITP family; and (v) conformational transitions in the C-terminal helix have specific functional involvements in PtdIns transfer activity. Taken together, these findings provide the first mechanistic description of key aspects of the PITP PtdIns/PtdCho exchange cycle and offer a rationale for the high conservation of particular sets of residues across evolutionarily distant members of the meta-zoan StART-like PITP family.

U2 - 10.1074/jbc.M117.791467

DO - 10.1074/jbc.M117.791467

M3 - Article

VL - 292

SP - 14438

EP - 14455

JO - Journal of Biological Chemistry

JF - Journal of Biological Chemistry

SN - 0021-9258

IS - 35

ER -