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Autoinhibition and activation mechanisms of the eukaryotic lipid flippase Drs2p-Cdc50p.

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Bai L, Kovach A, You Q, Hsu HC, Zhao G, Li H
OpenAccess logo Nat Commun 10 4142 (2019)
Cited: 26 times
EuropePMC logo PMID: 31515475

Abstract

The heterodimeric eukaryotic Drs2p-Cdc50p complex is a lipid flippase that maintains cell membrane asymmetry. The enzyme complex exists in an autoinhibited form in the absence of an activator and is specifically activated by phosphatidylinositol-4-phosphate (PI4P), although the underlying mechanisms have been unclear. Here we report the cryo-EM structures of intact Drs2p-Cdc50p isolated from S. cerevisiae in apo form and in the PI4P-activated form at 2.8 Å and 3.3 Å resolution, respectively. The structures reveal that the Drs2p C-terminus lines a long groove in the cytosolic regulatory region to inhibit the flippase activity. PIP4 binding in a cytosol-proximal membrane region triggers a 90° rotation of a cytosolic helix switch that is located just upstream of the inhibitory C-terminal peptide. The rotation of the helix switch dislodges the C-terminus from the regulatory region, activating the flippase.

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  1. Novel roles of phosphoinositides in signaling, lipid transport, and disease. Hammond GRV, Burke JE. Curr Opin Cell Biol 63 57-67 (2020)
  2. Mechanisms of Non-Vesicular Exchange of Lipids at Membrane Contact Sites: Of Shuttles, Tunnels and, Funnels. Egea PF. Front Cell Dev Biol 9 784367 (2021)
  3. Protein Adsorption on Solid Supported Membranes: Monitoring the Transport Activity of P-Type ATPases. Tadini-Buoninsegni F. Molecules 25 E4167 (2020)
  4. Transport Pathways That Contribute to the Cellular Distribution of Phosphatidylserine. Lenoir G, D'Ambrosio JM, Dieudonné T, Čopič A. Front Cell Dev Biol 9 737907 (2021)
  5. Lipid Transporters Beam Signals from Cell Membranes. Ristovski M, Farhat D, Bancud SEM, Lee JY. Membranes (Basel) 11 562 (2021)
  6. Reconstitution of ATP-dependent lipid transporters: gaining insight into molecular characteristics, regulation, and mechanisms. Herrera SA, Günther Pomorski T. Biosci Rep 43 BSR20221268 (2023)
  7. Regulation of phospholipid distribution in the lipid bilayer by flippases and scramblases. Sakuragi T, Nagata S. Nat Rev Mol Cell Biol (2023)

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  1. The endoplasmic reticulum P5A-ATPase is a transmembrane helix dislocase. McKenna MJ, Sim SI, Ordureau A, Wei L, Harper JW, Shao S, Park E. Science 369 eabc5809 (2020)
  2. Transport mechanism of P4 ATPase phosphatidylcholine flippases. Bai L, You Q, Jain BK, Duan HD, Kovach A, Graham TR, Li H. Elife 9 e62163 (2020)
  3. Aminoglycerophospholipid flipping and P4-ATPases in Toxoplasma gondii. Chen K, Günay-Esiyok Ö, Klingeberg M, Marquardt S, Pomorski TG, Gupta N. J Biol Chem 296 100315 (2021)
  4. Dynamic membranes: the multiple roles of P4 and P5 ATPases. López-Marqués RL, Davis JA, Harper JF, Palmgren M. Plant Physiol 185 619-631 (2021)
  5. Exofacial membrane composition and lipid metabolism regulates plasma membrane P4-ATPase substrate specificity. Jain BK, Roland BP, Graham TR. J Biol Chem 295 17997-18009 (2020)
  6. Lipid Transport by Candida albicans Dnf2 Is Required for Hyphal Growth and Virulence. Jain BK, Wagner AS, Reynolds TB, Graham TR. Infect Immun 90 e0041622 (2022)
  7. Structural insights into the activation of autoinhibited human lipid flippase ATP8B1 upon substrate binding. Cheng MT, Chen Y, Chen ZP, Liu X, Zhang Z, Chen Y, Hou WT, Zhou CZ. Proc Natl Acad Sci U S A 119 e2118656119 (2022)
  8. The P4-ATPase Drs2 interacts with and stabilizes the multisubunit tethering complex TRAPPIII in yeast. Pazos I, Puig-Tintó M, Betancur L, Cordero J, Jiménez-Menéndez N, Abella M, Hernández AC, Duran AG, Adachi-Fernández E, Belmonte-Mateos C, Sabido-Bozo S, Tosi S, Nezu A, Oliva B, Colombelli J, Graham TR, Yoshimori T, Muñiz M, Hamasaki M, Gallego O. EMBO Rep 24 e56134 (2023)
  9. ATP2, The essential P4-ATPase of malaria parasites, catalyzes lipid-stimulated ATP hydrolysis in complex with a Cdc50 β-subunit. Lamy A, Macarini-Bruzaferro E, Dieudonné T, Perálvarez-Marín A, Lenoir G, Montigny C, le Maire M, Vázquez-Ibar JL. Emerg Microbes Infect 10 132-147 (2021)
  10. Apically-located P4-ATPase1-Lem1 complex internalizes phosphatidylserine and regulates motility-dependent invasion and egress in Toxoplasma gondii. Chen K, Huang X, Distler U, Tenzer S, Günay-Esiyok Ö, Gupta N. Comput Struct Biotechnol J 21 1893-1906 (2023)
  11. Autoinhibition and regulation by phosphoinositides of ATP8B1, a human lipid flippase associated with intrahepatic cholestatic disorders. Dieudonné T, Herrera SA, Laursen MJ, Lejeune M, Stock C, Slimani K, Jaxel C, Lyons JA, Montigny C, Pomorski TG, Nissen P, Lenoir G. Elife 11 e75272 (2022)
  12. Cryo-EM of the ATP11C flippase reconstituted in Nanodiscs shows a distended phospholipid bilayer inner membrane around transmembrane helix 2. Nakanishi H, Hayashida K, Nishizawa T, Oshima A, Abe K. J Biol Chem 298 101498 (2022)
  13. Functional Analysis of the P-Type ATPases Apt2-4 from Cryptococcus neoformans by Heterologous Expression in Saccharomyces cerevisiae. Veit S, Laerbusch S, López-Marqués RL, Günther Pomorski T. J Fungi (Basel) 9 202 (2023)
  14. In Silico Assessment of the Lipid Fingerprint Signature of ATP2, the Essential P4-ATPase of Malaria Parasites. López-Martín M, Renault P, Giraldo J, Vázquez-Ibar JL, Perálvarez-Marín A. Membranes (Basel) 12 702 (2022)
  15. P-Type ATPase Apt1 of the Fungal Pathogen Cryptococcus neoformans Is a Lipid Flippase of Broad Substrate Specificity. Stanchev LD, Rizzo J, Peschel R, Pazurek LA, Bredegaard L, Veit S, Laerbusch S, Rodrigues ML, López-Marqués RL, Günther Pomorski T. J Fungi (Basel) 7 843 (2021)
  16. Structural basis of the P4B ATPase lipid flippase activity. Bai L, Jain BK, You Q, Duan HD, Takar M, Graham TR, Li H. Nat Commun 12 5963 (2021)
  17. Structure of the Wilson disease copper transporter ATP7B. Bitter RM, Oh S, Deng Z, Rahman S, Hite RK, Yuan P. Sci Adv 8 eabl5508 (2022)
  18. Yeast as a tool for membrane protein production and structure determination. Carlesso A, Delgado R, Ruiz Isant O, Uwangue O, Valli D, Bill RM, Hedfalk K. FEMS Yeast Res 22 foac047 (2022)


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