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Glutathione import in Haemophilus influenzae Rd is primed by the periplasmic heme-binding protein HbpA

Bjorn Vergauwen, Jonathan Elegheert, Ann Dansercoer UGent, Bart Devreese UGent and Savvas Savvides UGent (2010) PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA. 107(30). p.13270-13275
abstract
Glutathione (GSH) is a vital intracellular cysteine-containing tripeptide across all kingdoms of life and assumes a plethora of cellular roles. Such pleiotropic behavior relies on a finely tuned spatiotemporal distribution of glutathione and its conjugates, which is not only controlled by synthesis and breakdown, but also by transport. Here, we show that import of glutathione in the obligate human pathogen Haemophilus influenzae, a glutathione auxotrophe, is mediated by the ATP-binding cassette (ABC)-like dipeptide transporter DppBCDF, which is primed for glutathione transport by a dedicated periplasmic-binding protein (PBP). We have identified the periplasmic lipoprotein HbpA, a protein hitherto implicated in heme acquisition, as the cognate PBP that specifically binds reduced (GSH) and oxidized glutathione (GSSG) forms of glutathione with physiologically relevant affinity, while it exhibits marginal binding to hemin. Dissection of the ligand preferences of HbpA showed that HbpA does not recognize bulky glutathione S conjugates or glutathione derivatives with C-terminal modifications, consistent with the need for selective import of useful forms of glutathione and the concomitant exclusion of potentially toxic glutathione adducts. Structural studies of the highly homologous HbpA from Haemophilus parasuis in complex with GSSG have revealed the structural basis of the proposed novel function for HbpA-like proteins, thus allowing a delineation of highly conserved structure-sequence fingerprints for the entire family of HbpA proteins. Taken together, our studies unmask the main physiological role of HbpA and establish a paradigm for glutathione import in bacteria. Accordingly, we propose a name change for HbpA to glutathione-binding protein A.
Please use this url to cite or link to this publication:
author
organization
year
type
journalArticle (original)
publication status
published
subject
keyword
STRUCTURAL BASIS, YEAST SCHIZOSACCHAROMYCES-POMBE, DIPEPTIDE PERMEASE, PEPTIDE BINDING, TRANSPORT, IDENTIFICATION, OXIDATIVE STRESS, HYDROGEN-PEROXIDE, SACCHAROMYCES-CEREVISIAE, dipeptide permease, solute binding protein, GbpA, DppA, ESCHERICHIA-COLI K-12
journal title
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Proc. Natl. Acad. Sci. USA
volume
107
issue
30
pages
13270 - 13275
Web of Science type
Article
Web of Science id
000280602800018
JCR category
MULTIDISCIPLINARY SCIENCES
JCR impact factor
9.771 (2010)
JCR rank
3/56 (2010)
JCR quartile
1 (2010)
ISSN
0027-8424
DOI
10.1073/pnas.1005198107
language
English
UGent publication?
yes
classification
A1
copyright statement
I have transferred the copyright for this publication to the publisher
id
1089773
handle
http://hdl.handle.net/1854/LU-1089773
date created
2010-12-20 13:10:44
date last changed
2016-12-19 15:46:17
@article{1089773,
  abstract     = {Glutathione (GSH) is a vital intracellular cysteine-containing tripeptide across all kingdoms of life and assumes a plethora of cellular roles. Such pleiotropic behavior relies on a finely tuned spatiotemporal distribution of glutathione and its conjugates, which is not only controlled by synthesis and breakdown, but also by transport. Here, we show that import of glutathione in the obligate human pathogen Haemophilus influenzae, a glutathione auxotrophe, is mediated by the ATP-binding cassette (ABC)-like dipeptide transporter DppBCDF, which is primed for glutathione transport by a dedicated periplasmic-binding protein (PBP). We have identified the periplasmic lipoprotein HbpA, a protein hitherto implicated in heme acquisition, as the cognate PBP that specifically binds reduced (GSH) and oxidized glutathione (GSSG) forms of glutathione with physiologically relevant affinity, while it exhibits marginal binding to hemin. Dissection of the ligand preferences of HbpA showed that HbpA does not recognize bulky glutathione S conjugates or glutathione derivatives with C-terminal modifications, consistent with the need for selective import of useful forms of glutathione and the concomitant exclusion of potentially toxic glutathione adducts. Structural studies of the highly homologous HbpA from Haemophilus parasuis in complex with GSSG have revealed the structural basis of the proposed novel function for HbpA-like proteins, thus allowing a delineation of highly conserved structure-sequence fingerprints for the entire family of HbpA proteins. Taken together, our studies unmask the main physiological role of HbpA and establish a paradigm for glutathione import in bacteria. Accordingly, we propose a name change for HbpA to glutathione-binding protein A.},
  author       = {Vergauwen, Bjorn and Elegheert, Jonathan and Dansercoer, Ann and Devreese, Bart and Savvides, Savvas},
  issn         = {0027-8424},
  journal      = {PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA},
  keyword      = {STRUCTURAL BASIS,YEAST SCHIZOSACCHAROMYCES-POMBE,DIPEPTIDE PERMEASE,PEPTIDE BINDING,TRANSPORT,IDENTIFICATION,OXIDATIVE STRESS,HYDROGEN-PEROXIDE,SACCHAROMYCES-CEREVISIAE,dipeptide permease,solute binding protein,GbpA,DppA,ESCHERICHIA-COLI K-12},
  language     = {eng},
  number       = {30},
  pages        = {13270--13275},
  title        = {Glutathione import in Haemophilus influenzae Rd is primed by the periplasmic heme-binding protein HbpA},
  url          = {http://dx.doi.org/10.1073/pnas.1005198107},
  volume       = {107},
  year         = {2010},
}

Chicago
Vergauwen, Bjorn, Jonathan Elegheert, Ann Dansercoer, Bart Devreese, and Savvas Savvides. 2010. “Glutathione Import in Haemophilus Influenzae Rd Is Primed by the Periplasmic Heme-binding Protein HbpA.” Proceedings of the National Academy of Sciences of the United States of America 107 (30): 13270–13275.
APA
Vergauwen, B., Elegheert, J., Dansercoer, A., Devreese, B., & Savvides, S. (2010). Glutathione import in Haemophilus influenzae Rd is primed by the periplasmic heme-binding protein HbpA. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 107(30), 13270–13275.
Vancouver
1.
Vergauwen B, Elegheert J, Dansercoer A, Devreese B, Savvides S. Glutathione import in Haemophilus influenzae Rd is primed by the periplasmic heme-binding protein HbpA. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA. 2010;107(30):13270–5.
MLA
Vergauwen, Bjorn, Jonathan Elegheert, Ann Dansercoer, et al. “Glutathione Import in Haemophilus Influenzae Rd Is Primed by the Periplasmic Heme-binding Protein HbpA.” PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 107.30 (2010): 13270–13275. Print.