A mycobacterial ABC transporter mediates the uptake of hydrophilic compounds
Abstract
Mycobacterium tuberculosis (Mtb) is an obligate human pathogen and the causative agent of tuberculosis. Although Mtb can synthesize vitamin B12 (cobalamin) de novo, uptake of cobalamin has been linked to pathogenesis of tuberculosis. Mtb does not encode any characterized cobalamin transporter; however, the gene rv1819c was found to be essential for uptake of cobalamin. This result is difficult to reconcile with the original annotation of Rv1819c as a protein implicated in the transport of antimicrobial peptides such as bleomycin. In addition, uptake of cobalamin seems inconsistent with the amino acid sequence, which suggests that Rv1819c has a bacterial ATP-binding cassette (ABC)-exporter fold. In this paper, we present structures of Rv1819c, which reveal that the protein indeed contains the ABC-exporter fold, as well as a large water-filled cavity of about 7,700 Å, which enables the protein to transport the unrelated hydrophilic compounds bleomycin and cobalamin. On the basis of these structures, we propose that Rv1819c is a multi-solute transporter for hydrophilic molecules, analogous to the multidrug exporters of the ABC transporter family, which pump out structurally diverse hydrophobic compounds from cells.
- Authors:
-
- Univ. of Groningen (The Netherlands)
- SLAC National Accelerator Lab., Menlo Park, CA (United States); Stanford Univ., Palo Alto, CA (United States)
- Stockholm Univ. (Sweden)
- Univ. of Groningen (The Netherlands); Moscow Inst. of Physics and Technology, Dolgoprudny (Russia)
- Publication Date:
- Research Org.:
- SLAC National Accelerator Laboratory (SLAC), Menlo Park, CA (United States)
- Sponsoring Org.:
- European Molecular Microbiology Organization (EMBO); Netherlands Organization for Scientific Research (NWO); Swedish Research Council (VR); Carl Tryggers Foundation; USDOE Laboratory Directed Research and Development (LDRD) Program
- OSTI Identifier:
- 1616960
- Grant/Contract Number:
- AC02-76SF00515; 714.018.003; 723.014.002
- Resource Type:
- Accepted Manuscript
- Journal Name:
- Nature (London)
- Additional Journal Information:
- Journal Name: Nature (London); Journal Volume: 580; Journal Issue: 7803; Journal ID: ISSN 0028-0836
- Publisher:
- Nature Publishing Group
- Country of Publication:
- United States
- Language:
- English
- Subject:
- 59 BASIC BIOLOGICAL SCIENCES; Bacterial structural biology; Cryoelectron microscopy; Membrane proteins
Citation Formats
Rempel, S., Gati, C., Nijland, M., Thangaratnarajah, C., Karyolaimos, A., de Gier, J. W., Guskov, A., and Slotboom, D. J. A mycobacterial ABC transporter mediates the uptake of hydrophilic compounds. United States: N. p., 2020.
Web. doi:10.1038/s41586-020-2072-8.
Rempel, S., Gati, C., Nijland, M., Thangaratnarajah, C., Karyolaimos, A., de Gier, J. W., Guskov, A., & Slotboom, D. J. A mycobacterial ABC transporter mediates the uptake of hydrophilic compounds. United States. https://doi.org/10.1038/s41586-020-2072-8
Rempel, S., Gati, C., Nijland, M., Thangaratnarajah, C., Karyolaimos, A., de Gier, J. W., Guskov, A., and Slotboom, D. J. Wed .
"A mycobacterial ABC transporter mediates the uptake of hydrophilic compounds". United States. https://doi.org/10.1038/s41586-020-2072-8. https://www.osti.gov/servlets/purl/1616960.
@article{osti_1616960,
title = {A mycobacterial ABC transporter mediates the uptake of hydrophilic compounds},
author = {Rempel, S. and Gati, C. and Nijland, M. and Thangaratnarajah, C. and Karyolaimos, A. and de Gier, J. W. and Guskov, A. and Slotboom, D. J.},
abstractNote = {Mycobacterium tuberculosis (Mtb) is an obligate human pathogen and the causative agent of tuberculosis. Although Mtb can synthesize vitamin B12 (cobalamin) de novo, uptake of cobalamin has been linked to pathogenesis of tuberculosis. Mtb does not encode any characterized cobalamin transporter; however, the gene rv1819c was found to be essential for uptake of cobalamin. This result is difficult to reconcile with the original annotation of Rv1819c as a protein implicated in the transport of antimicrobial peptides such as bleomycin. In addition, uptake of cobalamin seems inconsistent with the amino acid sequence, which suggests that Rv1819c has a bacterial ATP-binding cassette (ABC)-exporter fold. In this paper, we present structures of Rv1819c, which reveal that the protein indeed contains the ABC-exporter fold, as well as a large water-filled cavity of about 7,700 Å, which enables the protein to transport the unrelated hydrophilic compounds bleomycin and cobalamin. On the basis of these structures, we propose that Rv1819c is a multi-solute transporter for hydrophilic molecules, analogous to the multidrug exporters of the ABC transporter family, which pump out structurally diverse hydrophobic compounds from cells.},
doi = {10.1038/s41586-020-2072-8},
journal = {Nature (London)},
number = 7803,
volume = 580,
place = {United States},
year = {Wed Mar 25 00:00:00 EDT 2020},
month = {Wed Mar 25 00:00:00 EDT 2020}
}
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Works referenced in this record:
Conformational dynamics of the ABC transporter McjD seen by single‐molecule FRET
journal, September 2018
- Husada, Florence; Bountra, Kiran; Tassis, Konstantinos
- The EMBO Journal, Vol. 37, Issue 21
Electrostatics of nanosystems: Application to microtubules and the ribosome
journal, August 2001
- Baker, N. A.; Sept, D.; Joseph, S.
- Proceedings of the National Academy of Sciences, Vol. 98, Issue 18, p. 10037-10041
AutoDock4 and AutoDockTools4: Automated docking with selective receptor flexibility
journal, December 2009
- Morris, Garrett M.; Huey, Ruth; Lindstrom, William
- Journal of Computational Chemistry, Vol. 30, Issue 16
E. coli Genome Manipulation by P1 Transduction
journal, May 2014
- Thomason, Lynn C.; Costantino, Nina; Court, Donald L.
- Current Protocols in Molecular Biology, Vol. 79, Issue 1
Functional and structural characterization of an ECF-type ABC transporter for vitamin B12
journal, May 2018
- Santos, Joana A.; Rempel, Stephan; Mous, Sandra TM
- eLife, Vol. 7
Functional Non-equivalence of ATP-binding Cassette Signature Motifs in the Transporter Associated with Antigen Processing (TAP)
journal, August 2004
- Chen, Min; Abele, Rupert; Tampé, Robert
- Journal of Biological Chemistry, Vol. 279, Issue 44
Construction of Escherichia coli K-12 in-frame, single-gene knockout mutants the Keio collection
journal, February 2006
- Baba, Tomoya; Ara, Takeshi; Hasegawa, Miki
- Molecular Systems Biology, Vol. 2, Article No. 2006.0008
Structural diversity of ABC transporters
journal, March 2014
- ter Beek, Josy; Guskov, Albert; Slotboom, Dirk Jan
- The Journal of General Physiology, Vol. 143, Issue 4
Exploring the gas access routes in a [NiFeSe] hydrogenase using crystals pressurized with krypton and oxygen
journal, August 2020
- Zacarias, Sónia; Temporão, Adriana; Carpentier, Philippe
- JBIC Journal of Biological Inorganic Chemistry, Vol. 25, Issue 6
Conformation space of a heterodimeric ABC exporter under turnover conditions
journal, July 2019
- Hofmann, Susanne; Januliene, Dovile; Mehdipour, Ahmad R.
- Nature, Vol. 571, Issue 7766
CTFFIND4: Fast and accurate defocus estimation from electron micrographs
journal, November 2015
- Rohou, Alexis; Grigorieff, Nikolaus
- Journal of Structural Biology, Vol. 192, Issue 2
Structure of the multidrug ABC transporter Sav1866 from Staphylococcus aureus in complex with AMP-PNP
journal, February 2007
- Dawson, Roger J. P.; Locher, Kaspar P.
- FEBS Letters, Vol. 581, Issue 5
Cysteine-mediated decyanation of vitamin B12 by the predicted membrane transporter BtuM
journal, August 2018
- Rempel, S.; Colucci, E.; de Gier, J. W.
- Nature Communications, Vol. 9, Issue 1
Structure of an antibacterial peptide ATP-binding cassette transporter in a novel outward occluded state
journal, June 2014
- Choudhury, H. G.; Tong, Z.; Mathavan, I.
- Proceedings of the National Academy of Sciences, Vol. 111, Issue 25
Crystal structures of a polypeptide processing and secretion transporter
journal, July 2015
- Lin, David Yin-wei; Huang, Shuo; Chen, Jue
- Nature, Vol. 523, Issue 7561
New tools for automated high-resolution cryo-EM structure determination in RELION-3
journal, November 2018
- Zivanov, Jasenko; Nakane, Takanori; Forsberg, Björn O.
- eLife, Vol. 7
Functional Characterization of SbmA, a Bacterial Inner Membrane Transporter Required for Importing the Antimicrobial Peptide Bac7(1-35)
journal, September 2013
- Runti, G.; Lopez Ruiz, M. d. C.; Stoilova, T.
- Journal of Bacteriology, Vol. 195, Issue 23
Effects of a detergent micelle environment on P-glycoprotein (ABCB1)-ligand interactions
journal, March 2017
- Shukla, Suneet; Abel, Biebele; Chufan, Eduardo E.
- Journal of Biological Chemistry, Vol. 292, Issue 17
Biotin Synthase Is Catalytic In Vivo, but Catalysis Engenders Destruction of the Protein
journal, April 2005
- Choi-Rhee, Eunjoo; Cronan, John E.
- Chemistry & Biology, Vol. 12, Issue 4
MotionCor2: anisotropic correction of beam-induced motion for improved cryo-electron microscopy
journal, February 2017
- Zheng, Shawn Q.; Palovcak, Eugene; Armache, Jean-Paul
- Nature Methods, Vol. 14, Issue 4
Molecular structure of human P-glycoprotein in the ATP-bound, outward-facing conformation
journal, January 2018
- Kim, Youngjin; Chen, Jue
- Science, Vol. 359, Issue 6378
Computational studies of polyurethanases from Pseudomonas
journal, January 2021
- do Canto, Vanessa Petry; Thompson, Claudia Elizabeth; Netz, Paulo Augusto
- Journal of Molecular Modeling, Vol. 27, Issue 2
CASTp 3.0: computed atlas of surface topography of proteins
journal, June 2018
- Tian, Wei; Chen, Chang; Lei, Xue
- Nucleic Acids Research, Vol. 46, Issue W1
Membrane reconstitution of ABC transporters and assays of translocator function
journal, January 2008
- Geertsma, Eric R.; Nik Mahmood, N. A. B.; Schuurman-Wolters, Gea K.
- Nature Protocols, Vol. 3, Issue 2
PARP1 exhibits enhanced association and catalytic efficiency with γH2A.X-nucleosome
journal, December 2019
- Sharma, Deepti; De Falco, Louis; Padavattan, Sivaraman
- Nature Communications, Vol. 10, Issue 1
Assembly of the Mycobacterial Cell Wall
journal, October 2015
- Jankute, Monika; Cox, Jonathan A. G.; Harrison, James
- Annual Review of Microbiology, Vol. 69, Issue 1
Structural insight into substrate and inhibitor discrimination by human P-glycoprotein
text, January 2019
- Alam, Amer; Kowal, Julia; Broude, Eugenia V.
- ETH Zurich
Cavin1 intrinsically disordered domains are essential for fuzzy electrostatic interactions and caveola formation
journal, February 2021
- Tillu, Vikas A.; Rae, James; Gao, Ya
- Nature Communications, Vol. 12, Issue 1
Bacterial uptake of aminoglycoside antibiotics.
journal, January 1987
- Taber, H. W.; Mueller, J. P.; Miller, P. F.
- Microbiological Reviews, Vol. 51, Issue 4
Structure of AMP-PNP-bound vitamin B12 transporter BtuCD–F
journal, September 2012
- Korkhov, Vladimir M.; Mireku, Samantha A.; Locher, Kaspar P.
- Nature, Vol. 490, Issue 7420
MolProbity : all-atom structure validation for macromolecular crystallography
journal, December 2009
- Chen, Vincent B.; Arendall, W. Bryan; Headd, Jeffrey J.
- Acta Crystallographica Section D Biological Crystallography, Vol. 66, Issue 1
A vitamin B 12 transporter in Mycobacterium tuberculosis
journal, February 2013
- Gopinath, Krishnamoorthy; Venclovas, Česlovas; Ioerger, Thomas R.
- Open Biology, Vol. 3, Issue 2
Structure of P-Glycoprotein Reveals a Molecular Basis for Poly-Specific Drug Binding
journal, March 2009
- Aller, S. G.; Yu, J.; Ward, A.
- Science, Vol. 323, Issue 5922
Features and development of Coot
journal, March 2010
- Emsley, P.; Lohkamp, B.; Scott, W. G.
- Acta Crystallographica Section D Biological Crystallography, Vol. 66, Issue 4
Bacterial uptake of aminoglycoside antibiotics.
journal, January 1987
- Taber, H. W.; Mueller, J. P.; Miller, P. F.
- Microbiological Reviews, Vol. 51, Issue 4
A vitamin B12 transporter in Mycobacterium tuberculosis
text, January 2013
- Gopinath, Krishnamoorthy; Venclovas, Česlovas; Ioerger, Thomas R.
- ETH Zurich
Vitamin B 12 metabolism in Mycobacterium tuberculosis
journal, November 2013
- Gopinath, Krishnamoorthy; Moosa, Atica; Mizrahi, Valerie
- Future Microbiology, Vol. 8, Issue 11
PHENIX: a comprehensive Python-based system for macromolecular structure solution
journal, January 2010
- Adams, Paul D.; Afonine, Pavel V.; Bunkóczi, Gábor
- Acta Crystallographica Section D Biological Crystallography, Vol. 66, Issue 2, p. 213-221
Identification and Characterization of a Novel FosA7 Member from Fosfomycin-Resistant Escherichia coli Clinical Isolates from Canadian Hospitals
journal, December 2020
- Milner, Kieran A.; Bay, Denice C.; Alexander, David
- Antimicrobial Agents and Chemotherapy, Vol. 65, Issue 1
ECF-Type ATP-Binding Cassette Transporters
journal, June 2019
- Rempel, S.; Stanek, W. K.; Slotboom, D. J.
- Annual Review of Biochemistry, Vol. 88, Issue 1
Solitary BioY Proteins Mediate Biotin Transport into Recombinant Escherichia coli
journal, July 2013
- Finkenwirth, F.; Kirsch, F.; Eitinger, T.
- Journal of Bacteriology, Vol. 195, Issue 18
Cryo-EM structure of human lysosomal cobalamin exporter ABCD4
journal, August 2019
- Xu, Da; Feng, Zhang; Hou, Wen-Tao
- Cell Research, Vol. 29, Issue 12
BacA, an ABC Transporter Involved in Maintenance of Chronic Murine Infections with Mycobacterium tuberculosis
journal, November 2008
- Domenech, Pilar; Kobayashi, Hajime; LeVier, Kristin
- Journal of Bacteriology, Vol. 191, Issue 2
Software tools for automated transmission electron microscopy
journal, May 2019
- Schorb, Martin; Haberbosch, Isabella; Hagen, Wim J. H.
- Nature Methods, Vol. 16, Issue 6
Structural insight into substrate and inhibitor discrimination by human P-glycoprotein
journal, February 2019
- Alam, Amer; Kowal, Julia; Broude, Eugenia
- Science, Vol. 363, Issue 6428
Structure of AMP-PNP–bound BtuCD and mechanism of ATP-powered vitamin B12 transport by BtuCD–F
journal, November 2014
- Korkhov, Vladimir M.; Mireku, Samantha A.; Veprintsev, Dmitry B.
- Nature Structural & Molecular Biology, Vol. 21, Issue 12
PHENIX: a comprehensive Python-based system for macromolecular structure solution.
text, January 2010
- Adams, Paul D.; Afonine, Pavel V.; Bunkóczi, Gábor
- Apollo - University of Cambridge Repository
Structure of AMP-PNP-bound BtuCD and mechanism of ATP-powered vitamin B12 transport by BtuCD-F
text, January 2014
- Korkhov, Vladimir M.; Mireku, Samantha A.; Veprintsev, Dmitry B.
- ETH Zurich
Works referencing / citing this record:
Structures of ABC transporters: handle with care
journal, November 2020
- Lewinson, Oded; Orelle, Cédric; Seeger, Markus A.
- FEBS Letters, Vol. 594, Issue 23