Disease mutations reveal residues critical to the interaction of P4-ATPases with lipid substrates
| Autor: | Stine A. Mikkelsen, Bente Vilsen, Jens Peter Andersen, Rasmus Gantzel, Anna L. Vestergaard, Louise S Mogensen, Robert S. Molday |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Models Molecular Arginine Protein Conformation Phospholipid Gene Expression lcsh:Medicine Plasma protein binding Article Substrate Specificity 03 medical and health sciences chemistry.chemical_compound Structure-Activity Relationship Protein structure Phosphatidylcholine Journal Article Animals Genetic Predisposition to Disease Phospholipid Transfer Proteins lcsh:Science Phospholipids Adenosine Triphosphatases Multidisciplinary Binding Sites lcsh:R Flippase Phosphatidylserine Lipid Metabolism Enzyme Activation Transmembrane domain 030104 developmental biology chemistry Mutation Biophysics Cattle lcsh:Q Protein Binding |
| Zdroj: | Scientific Reports, Vol 7, Iss 1, Pp 1-11 (2017) Scientific Reports 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, vol. 7, no. 1, doi: 10.1038/s41598-017-10741-z., pp. 10418 . https://doi.org/10.1038/s41598-017-10741-z 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, vol. 7, 10418 . https://doi.org/10.1038/s41598-017-10741-z |
| ISSN: | 2045-2322 |
| DOI: | 10.1038/s41598-017-10741-z |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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