リケラボ論文検索は、全国の大学リポジトリにある学位論文・教授論文を一括検索できる論文検索サービスです。

リケラボ 全国の大学リポジトリにある学位論文・教授論文を一括検索するならリケラボ論文検索大学・研究所にある論文を検索できる

リケラボ 全国の大学リポジトリにある学位論文・教授論文を一括検索するならリケラボ論文検索大学・研究所にある論文を検索できる

大学・研究所にある論文を検索できる 「Structural and functional analyses of eukaryotic MATE transporter」の論文概要。リケラボ論文検索は、全国の大学リポジトリにある学位論文・教授論文を一括検索できる論文検索サービスです。
リケラボ

コピーが完了しました

URLをコピーしました

論文の公開元へ論文の公開元へ
書き出し

Structural and functional analyses of eukaryotic MATE transporter

宮内, 弘剛 東京大学 DOI:10.15083/0002004770

2022.06.22

概要

Multidrug extrusion is the essential biological process for maintaining the cellular homeostasis. All domains of life have been developed and acquired strategies for elimination of harmful xenobiotics. One of the most important strategy for detoxification of xenobiotics is export them from the cells with membrane proteins called as multidrug transporters. There are six member of multidrug transporters and they work independently to achieve extrusion of xenobiotics. The membrane transporters are divided into two large groups, one is the primary active transporters which transport substrates coupling to ATP hydrolysis, and the other is the secondary active transporters which use chemical gradient across the membrane.

Multidrug And Toxic compounds Extrusion (MATE) transporters belong to the secondary active multidrug transporters. MATE transporters extrude various organic cations using the H+ or Na+ chemical gradients, and conduct the electroneutral antiport.

MATE transporters are conserved in all domains of life. In bacteria, they work as efflux pumps of xenobiotics including antibiotics, and they give bacteria multidrug resistance. In human body, MATE transporters are expressed at the kidney and the liver, and they export various clinical drugs, including cimetidine, metformin, procainamide, cephalexin, and acyclovir into urine and bile using H+ chemical gradient. Then MATE transporters determine the plasma concentration of these drugs, and MATE transporters are the important factor in the pharmacodynamics of clinical drugs. In plant, MATE transporters are suggested that they have various biological roles in addition to the xenobiotics extrusion, considering that more than 50 MATE paralogues exist in Arabidopsis thaliana. The plant MATE transporters mediate the transport process of secondary metabolites, such as nicotine, flavonoids and proanthocyanidin precursors, and plant hormones, including abscisic acid. Furthermore, plant MATE transporter mediate citrate export from the root cells for chelation of phytotoxic aluminum ions, confering tolerance towards harmful aluminum in acidic soils.

Based on the amino-acid similarity, MATE transporters are classified into three subfamilies; NorMtype MATE subfamily, DinF-type MATE subfamily, and eukaryotic MATE subfamily, respectively. All prokaryotic MATE transporters belong to either NorM-type MATE or DinF-type MATE subfamily, on the other hand, all MATE transporters expressed in eukaryotes belong to eukaryotic MATE subfamily.

The crystal structures of NorM-type and DinF-type MATE transporters have been reported, and then the detailed mechanisms of transport and substrate recognition of prokaryotic MATE transporters are being revealed gradually. Although structural bases of NorM-type and DinF-type have revealed, that gave us limited clues for understanding the detailed mechanism of eukaryotic MATE transproters because of their low amino-acid similarity. None of crystal structures of eukaryotic MATE transporters had been reported because of their difficulty in crystallization, so the detailed mechanism remains elusive.

Here we determined the crystal structure of AtDTX14 from Arabidopsis thaliana at 2.6 Å resolution as eukaryotic MATE transporter. The structure of AtDTX14 is composed of two lobes; N-lobe (TM1- 6), and C-lobe (TM7-12), as is observed in the structures of prokaryotic MATE transporters. The crystal structure of AtDTX14 suggested that the substrate binding pocket is located at the center of Clobe and the pair of acidic residues plays an important role in substate recognition and H+ binding. Molecular dynamics simulations and structure guided biochemical analyses proposed the detailed substrate extrusion mechanism, in which the protonation of that acidic residues induces the conformational change of TM7 and this makes the substrate binding pocket shrink. Furthermore, the molecular dynamics with external force proposed the inward-open state of AtDTX14 and the validity of the extracelluar gate is confirmed with the evolutionary coupling pair calculation analysis.

Structural and functional analyses of AtDTX14 gave us insight into the structural basis of transport cycle in eukaryotic MATE transporters.

論文の公開元へ

関連論文

関連論文をもっと見る

参考文献

1. Drew, D. & Boudker, O. Shared Molecular Mechanisms of Membrane Transporters. Annu. Rev. Biochem. 85, 543–572 (2016).

2. Rees, D. C., Johnson, E. & Lewinson, O. ABC transporters: The power to change. Nature Reviews Molecular Cell Biology 10, 218–227 (2009).

3. Morita, Y. et al. NorM, a putative multidrug efflux protein, of Vibrio parahaemolyticus and its homolog in Escherichia coli. Antimicrob. Agents Chemother. 42, 1778–82 (1998).

4. Su, X.-Z., Chen, J., Mizushima, T., Kuroda, T. & Tsuchiya, T. AbeM, an H-Coupled Acinetobacter baumannii Multidrug Efflux Pump Belonging to the MATE Family of Transporters. Antimicrob. Agents Chemother. 49, 4362–4364 (2005).

5. Braibant, M., Guilloteau, L. & Zygmunt, M. S. Functional characterization of Brucella melitensis NorMI, an efflux pump belonging to the multidrug and toxic compound extrusion family. Antimicrob. Agents Chemother. 46, 3050–3053 (2002).

6. Huda, M. N., Morita, Y., Kuroda, T., Mizushima, T. & Tsuchiya, T. Na+-driven multidrug efflux pump VcmA from Vibrio cholerae non-O1, a non- halophilic bacterium. FEMS Microbiol. Lett. 203, 235–239 (2001).

7. Kaatz, G. W., Mcaleese, F. & Seo, S. M. Multidrug Resistance in Staphylococcus aureus Due to Overexpression of a Novel Multidrug and Toxin Extrusion (MATE) Transport Protein. Antimicrob. Agents Chemother. 49, 1857– 1864 (2005).

8. McAleese, F. et al. A novel MATE family efflux pump contributes to the reduced susceptibility of laboratory-derived Staphylococcus aureus mutants to tigecycline. Antimicrob. Agents Chemother. 49, 1865–1871 (2005).

9. Otsuka, M. et al. A human transporter protein that mediates the final excretion step for toxic organic cations. Proc Natl Acad Sci U S A 102, 17923– 17928 (2005).

10. Tanihara, Y. et al. Substrate specificity of MATE1 and MATE2-K, human multidrug and toxin extrusions/H + -organic cation antiporters. Biochem. Pharmacol. 74, 359–371 (2007).

11. Masuda, S. et al. Identification and functional characterization of a new human kidney-specific H+/organic cation antiporter, kidney-specific multidrug and toxin extrusion 2. J. Am. Soc. Nephrol. 17, 2127–35 (2006).

12. Yokoo, S. et al. Differential contribution of organic cation transporters, OCT2 and MATE1, in platinum agent-induced nephrotoxicity. Biochem. Pharmacol. 74, 477–487 (2007).

13. Hvorup, R. N. et al. The multidrug/oligosaccharidyllipid/polysaccharide (MOP) exporter superfamily. Eur. J. Biochem. 270, 799–813 (2003).

14. Morita, M. et al. Vacuolar transport of nicotine is mediated by a multidrug and toxic compound extrusion (MATE) transporter in Nicotiana tabacum.

15. Thompson, E. P., Wilkins, C., Demidchik, V., Davies, J. M. & Glover, B. J. An Arabidopsis flavonoid transporter is required for anther dehiscence and pollen development. J. Exp. Bot. 61, 439–51 (2010).

16. Marinova, K. et al. The Arabidopsis MATE Transporter TT12 Acts as a Vacuolar Flavonoid/H+-Antiporter Active in Proanthocyanidin-Accumulating Cells of the Seed Coat. PLANT CELL ONLINE 19, 2023–2038 (2007).

17. Li, L., He, Z., Pandey, G. K., Tsuchiya, T. & Luan, S. Functional cloning and characterization of a plant efflux carrier for multidrug and heavy metal detoxification. J. Biol. Chem. 277, 5360–5368 (2002).

18. Zhang, H. et al. A DTX/MATE-type transporter facilitates abscisic acid efflux and modulates ABA sensitivity and drought tolerance in Arabidopsis. Mol. Plant 7, 1522–1532 (2014).

19. Durrett, T. P., Gassmann, W. & Rogers, E. E. The FRD3-mediated efflux of citrate into the root vasculature is necessary for efficient iron translocation. Plant Physiol. 144, 197–205 (2007).

20. Liu, J., Magalhaes, J. V., Shaff, J. & Kochian, L. V. Aluminumactivated citrate and malate transporters from the MATE and ALMT families function independently to confer Arabidopsis aluminum tolerance. Plant J. 57, 389–399 (2009).

21. Pineau, C. et al. Natural Variation at the FRD3 MATE Transporter Locus Reveals Cross-Talk between Fe Homeostasis and Zn Tolerance in Arabidopsis thaliana. PLoS Genet. 8, e1003120 (2012).

22. Omote, H., Hiasa, M., Matsumoto, T., Otsuka, M. & Moriyama, Y. The MATE proteins as fundamental transporters of metabolic and xenobiotic organic cations. Trends Pharmacol. Sci. 27, 587–593 (2006).

23. Yan, N. Structural Biology of the Major Facilitator Superfamily Transporters. Annu. Rev. Biophys. 44, 257–283 (2015).

24. Brown, M. H., Paulsen, I. T. & Skurray, R. A. The multidrug efflux protein NorM is a prototype of a new family of transporters [2]. Mol. Microbiol. 31, 394–395 (1999).

25. He, X. et al. Structure of a cation-bound multidrug and toxic compound extrusion transporter. Nature 467, 991–4 (2010).

26. Lu, M. et al. Structures of a Na + -coupled, substrate-bound MATE multidrug transporter. Proc. Natl. Acad. Sci. 110, 2099–2104 (2013).

27. Radchenko, M. et al. Structural basis for the blockade of MATE multidrug efflux pumps. Nat. Commun. 6, 7995 (2015).

28. Nie, L. et al. Identification of the High-affinity Substrate-binding Site of the Multidrug and Toxic Compound Extrusion (MATE) Family Transporter from Pseudomonas stutzeri. J. Biol. Chem. 291, 15503–15514 (2016).

29. Eisinger, M. L., Nie, L., Dörrbaum, A. R., Langer, J. D. & Michel, H. The Xenobiotic Extrusion Mechanism of the MATE Transporter NorM_PS from Pseudomonas stutzeri. J. Mol. Biol. 430, 1311–1323 (2018).

30. Tanaka, Y. et al. Structural basis for the drug extrusion mechanism by a MATE multidrug transporter. Nature 496, 247–51 (2013).

31. Lu, M., Radchenko, M., Symersky, J., Nie, R. & Guo, Y. Structural insights into H+-coupled multidrug extrusion by a MATE transporter. Nat. Struct. Mol. Biol. 20, 1310–7 (2013).

32. Radchenko, M., Symersky, J., Nie, R. & Lu, M. Structural basis for the blockade of MATE multidrug efflux pumps. Nat. Commun. 6, 7995 (2015).

33. Kusakizako, T. et al. Structural Basis of H +-Dependent Conformational Change in a Bacterial MATE Transporter. Structure 27, 293–301 (2019).

34. Matsumoto, T., Kanamoto, T., Otsuka, M., Omote, H. & Moriyama, Y. Role of glutamate residues in substrate recognition by human MATE1 polyspecific H+/organic cation exporter. Am. J. Physiol. Cell Physiol. 294, C1074-8 (2008).

35. Li, R. et al. ADP1 Affects Plant Architecture by Regulating Local Auxin Biosynthesis. PLoS Genet. 10, e1003954 (2014).

36. Hattori, M., Hibbs, R. E. & Gouaux, E. A Fluorescence-Detection Size-Exclusion Chromatography-Based Thermostability Assay for Membrane Protein Precrystallization Screening. Structure 20, (2012).

37. Caffrey, M. & Cherezov, V. Crystallizing membrane proteins using lipidic mesophases. Nat. Protoc. 4, 706–31 (2009).

38. Ueno, G. et al. Remote access and automation of SPring-8 MX beamlines. in AIP Conference Proceedings 1741, (2016).

39. Yamashita, K., Hirata, K. & Yamamoto, M. KAMO: towards automated data processing for microcrystals. Res. Pap. Acta Cryst 74, 441–449 (2018).

40. Kabsch, W. XDS. Acta Crystallogr. Sect. D Biol. Crystallogr. 66, 125–132 (2010).

41. Vagin, A. & Teplyakov, A. MOLREP: an Automated Program for Molecular Replacement. J. Appl. Cryst 30, 1022–1025 (1997).

42. Murshudov, G. N., Vagin, A. ! A. & Dodson, E. J. Refinement of Macromolecular Structures by the Maximum-Likelihood Method. Acta Cryst 53, 240–255 (1997).

43. Emsley, P., Lohkamp, B., Scott, W. G. & Cowtan, K. Features and development of Coot. Acta Crystallogr. D. Biol. Crystallogr. 66, 486–501 (2010).

44. Adams, P. D. et al. PHENIX: building new software for automated crystallographic structure determination. Res. Pap. PHENIX Acta Cryst (1948).

45. Lu, M. Structures of multidrug and toxic compound extrusion transporters and their mechanistic implications. Channels (Austin). 6950, (2015).

46. Phillips, J. C. et al. Scalable molecular dynamics with NAMD. J. Comput. Chem. 26, 1781–1802 (2005).

47. Humphrey, W., Dalke, A. & Schulten, K. VMD: Visual molecular dynamics. J. Mol. Graph. 14, 33–38 (1996).

48. Best, R. B. et al. Optimization of the additive CHARMM all-atom protein force field targeting improved sampling of the backbone φ, ψ and sidechain χ(1) and χ(2) dihedral angles. J. Chem. Theory Comput. 8, 3257–3273 (2012).

49. Feller, S. E., Zhang, Y., Pastor, R. W. & Brooks, B. R. Constant pressure molecular dynamics simulation: The Langevin piston method. J. Chem. Phys. 103, 4613–4621 (1995).

50. Darden, T., York, D. & Pedersen, L. Particle mesh Ewald: An N ⋅ log( N ) method for Ewald sums in large systems. J. Chem. Phys. 98, 10089– 10092 (1993).

51. Kuk, A. C. Y., Mashalidis, E. H. & Lee, S.-Y. Crystal structure of the MOP flippase MurJ in an inward-facing conformation. Nat. Struct. Mol. Biol. 24, 171–176 (2016).

52. Krissinel, E. et al. Secondary-structure matching (SSM), a new tool for fast protein structure alignment in three dimensions. Acta Crystallogr. Sect. D Biol. Crystallogr. 60, 2256–2268 (2004).

53. Marks, D. S. et al. Protein 3D Structure Computed from Evolutionary Sequence Variation. PLoS One 6, (2011).

54. Hopf, T. A. et al. Three-Dimensional Structures of Membrane Proteins from Genomic Sequencing. Cell 149, 1607–1621 (2012).

55. Šali, A. & Blundell, T. L. Comparative Protein Modelling by Satisfaction of Spatial Restraints. J. Mol. Biol. 234, 779–815 (1993).

56. Tanaka, Y., Iwaki, S. & Tsukazaki, T. Crystal Structure of a Plant Multidrug and Toxic Compound Extrusion Family Protein. Structure 25, 1455- 1460.e2 (2017).

参考文献をもっと見る