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Molecular basis for the binding and modulation of V-ATPase by a bacterial effector protein.

Zhao J, Beyrakhova K, Liu Y, Alvarez CP, Bueler SA, Xu L, Xu C, Boniecki MT, Kanelis V, Luo ZQ, Cygler M, Rubinstein JL
PLoS Pathog 13 e1006394 (2017)
Related entries: 5uf5, 5ufk, 5voy, 5voz

Cited: 33 times
EuropePMC logo PMID: 28570695

Abstract

Intracellular pathogenic bacteria evade the immune response by replicating within host cells. Legionella pneumophila, the causative agent of Legionnaires' Disease, makes use of numerous effector proteins to construct a niche supportive of its replication within phagocytic cells. The L. pneumophila effector SidK was identified in a screen for proteins that reduce the activity of the proton pumping vacuolar-type ATPases (V-ATPases) when expressed in the yeast Saccharomyces cerevisae. SidK is secreted by L. pneumophila in the early stages of infection and by binding to and inhibiting the V-ATPase, SidK reduces phagosomal acidification and promotes survival of the bacterium inside macrophages. We determined crystal structures of the N-terminal region of SidK at 2.3 Å resolution and used single particle electron cryomicroscopy (cryo-EM) to determine structures of V-ATPase:SidK complexes at ~6.8 Å resolution. SidK is a flexible and elongated protein composed of an α-helical region that interacts with subunit A of the V-ATPase and a second region of unknown function that is flexibly-tethered to the first. SidK binds V-ATPase strongly by interacting via two α-helical bundles at its N terminus with subunit A. In vitro activity assays show that SidK does not inhibit the V-ATPase completely, but reduces its activity by ~40%, consistent with the partial V-ATPase deficiency phenotype its expression causes in yeast. The cryo-EM analysis shows that SidK reduces the flexibility of the A-subunit that is in the 'open' conformation. Fluorescence experiments indicate that SidK binding decreases the affinity of V-ATPase for a fluorescent analogue of ATP. Together, these results reveal the structural basis for the fine-tuning of V-ATPase activity by SidK.

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  1. Regulation of V-ATPase Activity and Organelle pH by Phosphatidylinositol Phosphate Lipids. Banerjee S, Kane PM. Front Cell Dev Biol 8 510 (2020)
  2. Formation of the Legionella Replicative Compartment at the Crossroads of Retrograde Trafficking. Bärlocher K, Welin A, Hilbi H. Front Cell Infect Microbiol 7 482 (2017)
  3. Determinants of Phagosomal pH During Host-Pathogen Interactions. Westman J, Grinstein S. Front Cell Dev Biol 8 624958 (2020)
  4. Tiny architects: biogenesis of intracellular replicative niches by bacterial pathogens. Martinez E, Siadous FA, Bonazzi M. FEMS Microbiol Rev 42 425-447 (2018)
  5. Structural Features of Apicomplexan Pore-Forming Proteins and Their Roles in Parasite Cell Traversal and Egress. Guerra AJ, Carruthers VB. Toxins (Basel) 9 E265 (2017)
  6. A review of TNP-ATP in protein binding studies: benefits and pitfalls. Woodbury DJ, Whitt EC, Coffman RE. Biophys Rep (N Y) 1 100012 (2021)
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  8. Eat or Be Eaten: Strategies Used by Legionella to Acquire Host-Derived Nutrients and Evade Lysosomal Degradation. Shames SR. Infect Immun 91 e0044122 (2023)
  9. Host-directed therapy for bacterial infections -Modulation of the phagolysosome pathway. Taya T, Teruyama F, Gojo S. Front Immunol 14 1227467 (2023)

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  1. Structure of V-ATPase from the mammalian brain. Abbas YM, Wu D, Bueler SA, Robinson CV, Rubinstein JL. Science 367 1240-1246 (2020)
  2. Structures of a Complete Human V-ATPase Reveal Mechanisms of Its Assembly. Wang L, Wu D, Robinson CV, Wu H, Fu TM. Mol Cell 80 501-511.e3 (2020)
  3. A Global Ramachandran Score Identifies Protein Structures with Unlikely Stereochemistry. Sobolev OV, Afonine PV, Moriarty NW, Hekkelman ML, Joosten RP, Perrakis A, Adams PD. Structure 28 1249-1258.e2 (2020)
  4. Mycobacterium tuberculosis Controls Phagosomal Acidification by Targeting CISH-Mediated Signaling. Queval CJ, Song OR, Carralot JP, Saliou JM, Bongiovanni A, Deloison G, Deboosère N, Jouny S, Iantomasi R, Delorme V, Debrie AS, Park SJ, Gouveia JC, Tomavo S, Brosch R, Yoshimura A, Yeramian E, Brodin P. Cell Rep 20 3188-3198 (2017)
  5. PIKfyve/Fab1 is required for efficient V-ATPase and hydrolase delivery to phagosomes, phagosomal killing, and restriction of Legionella infection. Buckley CM, Heath VL, Guého A, Bosmani C, Knobloch P, Sikakana P, Personnic N, Personnic N, Dove SK, Michell RH, Meier R, Hilbi H, Soldati T, Insall RH, King JS. PLoS Pathog 15 e1007551 (2019)
  6. Bafilomycin A1 enhances NLRP3 inflammasome activation in human monocytes independent of lysosomal acidification. Yu S, Green J, Wellens R, Lopez-Castejon G, Brough D. FEBS J 288 3186-3196 (2021)
  7. Coordinated conformational changes in the V1 complex during V-ATPase reversible dissociation. Vasanthakumar T, Keon KA, Bueler SA, Jaskolka MC, Rubinstein JL. Nat Struct Mol Biol 29 430-439 (2022)
  8. A distinct inhibitory mechanism of the V-ATPase by Vibrio VopQ revealed by cryo-EM. Peng W, Casey AK, Fernandez J, Carpinone EM, Servage KA, Chen Z, Li Y, Tomchick DR, Starai VJ, Orth K. Nat Struct Mol Biol 27 589-597 (2020)
  9. New Global Insights on the Regulation of the Biphasic Life Cycle and Virulence Via ClpP-Dependent Proteolysis in Legionella pneumophila. Ge Z, Yuan P, Chen L, Chen J, Shen D, She Z, Lu Y. Mol Cell Proteomics 21 100233 (2022)
  10. Wolbachia depletion blocks transmission of lymphatic filariasis by preventing chitinase-dependent parasite exsheathment. Quek S, Cook DAN, Wu Y, Marriott AE, Steven A, Johnston KL, Ford L, Archer J, Hemingway J, Ward SA, Wagstaff SC, Turner JD, Taylor MJ. Proc Natl Acad Sci U S A 119 e2120003119 (2022)
  11. Streptolysin S targets the sodium-bicarbonate cotransporter NBCn1 to induce inflammation and cytotoxicity in human keratinocytes during Group A Streptococcal infection. Hammers DE, Donahue DL, Tucker ZD, Ashfeld BL, Ploplis VA, Castellino FJ, Lee SW. Front Cell Infect Microbiol 12 1002230 (2022)
  12. CryoEM of endogenous mammalian V-ATPase interacting with the TLDc protein mEAK-7. Tan YZ, Abbas YM, Wu JZ, Wu D, Keon KA, Hesketh GG, Bueler SA, Gingras AC, Robinson CV, Grinstein S, Rubinstein JL. Life Sci Alliance 5 e202201527 (2022)
  13. Replicative Acinetobacter baumannii strains interfere with phagosomal maturation by modulating the vacuolar pH. Distel JS, Di Venanzio G, Mackel JJ, Rosen DA, Feldman MF. PLoS Pathog 19 e1011173 (2023)
  14. A model for collagen secretion by intercompartmental continuities. Bunel L, Pincet L, Malhotra V, Raote I, Pincet F. Proc Natl Acad Sci U S A 121 e2310404120 (2024)


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