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

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Grabon , A , Orlowski , A , Tripathi , A , Vuorio , J , Javanainen , M , Rog , T , Lönnfors , M , McDermott , M I , Siebert , G , Somerharju , P , Vattulainen , I & Bankaitis , V A 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

Title: Dynamics and energetics of the mammalian phosphatidylinositol transfer protein phospholipid exchange cycle
Author: Grabon, Aby; Orlowski, Adam; Tripathi, Ashutosh; Vuorio, Joni; Javanainen, Matti; Rog, Tomasz; Lönnfors, Max; McDermott, Mark I.; Siebert, Garland; Somerharju, Pentti; Vattulainen, Ilpo; Bankaitis, Vytas A.
Contributor organization: Department of Physics
Department of Biochemistry and Developmental Biology
Date: 2017-09-01
Language: eng
Number of pages: 18
Belongs to series: Journal of Biological Chemistry
ISSN: 0021-9258
DOI: https://doi.org/10.1074/jbc.M117.791467
URI: http://hdl.handle.net/10138/312495
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 alpha, 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 alpha lipid exchange cycle: (i) interaction of PITP alpha with the membrane is spontaneous and mediated by four specific protein substructures; (ii) the ability of PITP alpha 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 alpha; (iv) the trajectory of PtdIns or PtdCho into and through the lipidbinding pocket is chaperoned by sets of PITP alpha 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 alpha PtdIns/PtdCho exchange cycle and offer a rationale for the high conservation of particular sets of residues across evolutionarily distant members of the metazoan StART-like PITP family.
1182 Biochemistry, cell and molecular biology
116 Chemical sciences
Peer reviewed: Yes
Usage restriction: openAccess
Self-archived version: publishedVersion

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