Disease mutations reveal residues critical to the interaction of P4-ATPases with lipid substrates

Research output: Contribution to journalJournal articleResearchpeer-review

Standard

Disease mutations reveal residues critical to the interaction of P4-ATPases with lipid substrates. / Gantzel, Rasmus H; Mogensen, Louise S; Mikkelsen, Stine A; Vilsen, Bente; Molday, Robert S; Vestergaard, Anna L; Andersen, Jens P.

In: Scientific Reports, Vol. 7, 10418, 05.09.2017.

Research output: Contribution to journalJournal articleResearchpeer-review

Harvard

Gantzel, RH, Mogensen, LS, Mikkelsen, SA, Vilsen, B, Molday, RS, Vestergaard, AL & Andersen, JP 2017, 'Disease mutations reveal residues critical to the interaction of P4-ATPases with lipid substrates', Scientific Reports, vol. 7, 10418. https://doi.org/10.1038/s41598-017-10741-z

APA

Gantzel, R. H., Mogensen, L. S., Mikkelsen, S. A., Vilsen, B., Molday, R. S., Vestergaard, A. L., & Andersen, J. P. (2017). Disease mutations reveal residues critical to the interaction of P4-ATPases with lipid substrates. Scientific Reports, 7, [10418]. https://doi.org/10.1038/s41598-017-10741-z

Vancouver

Gantzel RH, Mogensen LS, Mikkelsen SA, Vilsen B, Molday RS, Vestergaard AL et al. Disease mutations reveal residues critical to the interaction of P4-ATPases with lipid substrates. Scientific Reports. 2017 Sep 5;7. 10418. https://doi.org/10.1038/s41598-017-10741-z

Author

Gantzel, Rasmus H ; Mogensen, Louise S ; Mikkelsen, Stine A ; Vilsen, Bente ; Molday, Robert S ; Vestergaard, Anna L ; Andersen, Jens P. / Disease mutations reveal residues critical to the interaction of P4-ATPases with lipid substrates. In: Scientific Reports. 2017 ; Vol. 7.

Bibtex

@article{c785b7131bd24672907354c7c84c8c03,
title = "Disease mutations reveal residues critical to the interaction of P4-ATPases with lipid substrates",
abstract = "Phospholipid flippases (P4-ATPases) translocate specific phospholipids from the exoplasmic to the cytoplasmic leaflet of membranes. While there is good evidence that the overall molecular structure of flippases is similar to that of P-type ATPase ion-pumps, the transport pathway for the {"}giant{"} lipid substrate has not been determined. ATP8A2 is a flippase with selectivity toward phosphatidylserine (PS), possessing a net negatively charged head group, whereas ATP8B1 exhibits selectivity toward the electrically neutral phosphatidylcholine (PC). Setting out to elucidate the functional consequences of flippase disease mutations, we have identified residues of ATP8A2 that are critical to the interaction with the lipid substrate during the translocation process. Among the residues pinpointed are I91 and L308, which are positioned near proposed translocation routes through the protein. In addition we pinpoint two juxtaposed oppositely charged residues, E897 and R898, in the exoplasmic loop between transmembrane helices 5 and 6. The glutamate is conserved between PS and PC flippases, whereas the arginine is replaced by a negatively charged aspartate in ATP8B1. Our mutational analysis suggests that the glutamate repels the PS head group, whereas the arginine minimizes this repulsion in ATP8A2, thereby contributing to control the entry of the phospholipid substrate into the translocation pathway.",
author = "Gantzel, {Rasmus H} and Mogensen, {Louise S} and Mikkelsen, {Stine A} and Bente Vilsen and Molday, {Robert S} and Vestergaard, {Anna L} and Andersen, {Jens P}",
year = "2017",
month = sep,
day = "5",
doi = "10.1038/s41598-017-10741-z",
language = "English",
volume = "7",
journal = "Scientific Reports",
issn = "2045-2322",
publisher = "nature publishing group",

}

RIS

TY - JOUR

T1 - Disease mutations reveal residues critical to the interaction of P4-ATPases with lipid substrates

AU - Gantzel, Rasmus H

AU - Mogensen, Louise S

AU - Mikkelsen, Stine A

AU - Vilsen, Bente

AU - Molday, Robert S

AU - Vestergaard, Anna L

AU - Andersen, Jens P

PY - 2017/9/5

Y1 - 2017/9/5

N2 - Phospholipid flippases (P4-ATPases) translocate specific phospholipids from the exoplasmic to the cytoplasmic leaflet of membranes. While there is good evidence that the overall molecular structure of flippases is similar to that of P-type ATPase ion-pumps, the transport pathway for the "giant" lipid substrate has not been determined. ATP8A2 is a flippase with selectivity toward phosphatidylserine (PS), possessing a net negatively charged head group, whereas ATP8B1 exhibits selectivity toward the electrically neutral phosphatidylcholine (PC). Setting out to elucidate the functional consequences of flippase disease mutations, we have identified residues of ATP8A2 that are critical to the interaction with the lipid substrate during the translocation process. Among the residues pinpointed are I91 and L308, which are positioned near proposed translocation routes through the protein. In addition we pinpoint two juxtaposed oppositely charged residues, E897 and R898, in the exoplasmic loop between transmembrane helices 5 and 6. The glutamate is conserved between PS and PC flippases, whereas the arginine is replaced by a negatively charged aspartate in ATP8B1. Our mutational analysis suggests that the glutamate repels the PS head group, whereas the arginine minimizes this repulsion in ATP8A2, thereby contributing to control the entry of the phospholipid substrate into the translocation pathway.

AB - Phospholipid flippases (P4-ATPases) translocate specific phospholipids from the exoplasmic to the cytoplasmic leaflet of membranes. While there is good evidence that the overall molecular structure of flippases is similar to that of P-type ATPase ion-pumps, the transport pathway for the "giant" lipid substrate has not been determined. ATP8A2 is a flippase with selectivity toward phosphatidylserine (PS), possessing a net negatively charged head group, whereas ATP8B1 exhibits selectivity toward the electrically neutral phosphatidylcholine (PC). Setting out to elucidate the functional consequences of flippase disease mutations, we have identified residues of ATP8A2 that are critical to the interaction with the lipid substrate during the translocation process. Among the residues pinpointed are I91 and L308, which are positioned near proposed translocation routes through the protein. In addition we pinpoint two juxtaposed oppositely charged residues, E897 and R898, in the exoplasmic loop between transmembrane helices 5 and 6. The glutamate is conserved between PS and PC flippases, whereas the arginine is replaced by a negatively charged aspartate in ATP8B1. Our mutational analysis suggests that the glutamate repels the PS head group, whereas the arginine minimizes this repulsion in ATP8A2, thereby contributing to control the entry of the phospholipid substrate into the translocation pathway.

U2 - 10.1038/s41598-017-10741-z

DO - 10.1038/s41598-017-10741-z

M3 - Journal article

C2 - 28874751

VL - 7

JO - Scientific Reports

JF - Scientific Reports

SN - 2045-2322

M1 - 10418

ER -

ID: 183159647