NDLI: Two-gate mechanism for phospholipid selection and transport by type IV P-type ATPases

Content Provider	PubMed Central
Author	Baldridge, Ryan D. Graham, Todd R.
Abstract	Most P-type ATPases pump specific cations or heavy metals across a membrane to form ion gradients. However, the type IV P-type ATPases evolved the ability to transport specific phospholipid substrates rather than cations and function to establish plasma membrane asymmetry in eukaryotic cells. The mechanism for how a P-type ATPase, or any other transporter, can recognize and flip a phospholipid substrate is unclear. Here, through a combination of genetic screening and directed mutagenesis with the type IV P-type ATPases Dnf1 and Drs2 from budding yeast, we identify more than a dozen residues that determine headgroup specificity for phospholipid transport. These residues cluster at two interfacial regions flanking transmembrane segments 1–4 and lie outside of the canonical substrate binding site operating in cation pumps. Our data imply the presence of two substrate-selecting gates acting sequentially on opposite sides of the membrane: an entry gate, where phospholipid is initially selected from the extracellular leaflet, and an exit gate at the cytosolic leaflet. The entry and exit gates act cooperatively but imperfectly, with neither being able to restrict phosphatidylserine selection completely when the opposing gate is tuned to permit it. This work describes a unique transport mechanism for a P-type ATPase and provides insight into how integral membrane proteins can recognize and transport phospholipid substrate across a lipid bilayer.
Related Links	http://dx.doi.org/10.1073/pnas.1216948110
Starting Page	358
File Format	PDF
ISSN	00278424
e-ISSN	10916490
Journal	Proceedings of the National Academy of Sciences of the United States of America
Issue Number	5
Volume Number	110
Language	English
Publisher	National Academy of Sciences
Publisher Date	2013-01-29
Access Restriction	Open
Rights Holder	National Academy of Sciences
Subject Keyword	General Research in Higher Education
Content Type	Text
Resource Type	Article
Subject	Multidisciplinary

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