Glutathione import in Haemophilus influenzae Rd is primed by the periplasmic heme-binding protein HbpA.
Proceedings of the National Academy of Sciences. 2010-07-13; 107(30): 13270-13275
DOI: 10.1073/pnas.1005198107
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1. Proc Natl Acad Sci U S A. 2010 Jul 27;107(30):13270-5. doi:
10.1073/pnas.1005198107. Epub 2010 Jul 13.
Glutathione import in Haemophilus influenzae Rd is primed by the periplasmic
heme-binding protein HbpA.
Vergauwen B(1), Elegheert J, Dansercoer A, Devreese B, Savvides SN.
Author information:
(1)Laboratory for Protein Biochemistry and Biomolecular Engineering (L-ProBE),
Department of Biochemistry and Microbiology, Ghent University, 9000 Ghent,
Belgium.
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.
DOI: 10.1073/pnas.1005198107
PMCID: PMC2922120
PMID: 20628015 [Indexed for MEDLINE]