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PDBsum entry 2lw3
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Membrane protein
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PDB id
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2lw3
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References listed in PDB file
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Key reference
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Title
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Discovery of a siderophore export system essential for virulence of mycobacterium tuberculosis.
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Authors
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R.M.Wells,
C.M.Jones,
Z.Xi,
A.Speer,
O.Danilchanka,
K.S.Doornbos,
P.Sun,
F.Wu,
C.Tian,
M.Niederweis.
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Ref.
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Plos Pathog, 2013,
9,
e1003120.
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PubMed id
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Abstract
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Iron is an essential nutrient for most bacterial pathogens, but is restricted by
the host immune system. Mycobacterium tuberculosis (Mtb) utilizes two classes of
small molecules, mycobactins and carboxymycobactins, to capture iron from the
human host. Here, we show that an Mtb mutant lacking the mmpS4 and mmpS5 genes
did not grow under low iron conditions. A cytoplasmic iron reporter indicated
that the double mutant experienced iron starvation even under high-iron
conditions. Loss of mmpS4 and mmpS5 did not change uptake of carboxymycobactin
by Mtb. Thin layer chromatography showed that the ΔmmpS4/S5 mutant was strongly
impaired in biosynthesis and secretion of siderophores. Pull-down experiments
with purified proteins demonstrated that MmpS4 binds to a periplasmic loop of
the associated transporter protein MmpL4. This interaction was corroborated by
genetic experiments. While MmpS5 interacted only with MmpL5, MmpS4 interacted
with both MmpL4 and MmpL5. These results identified MmpS4/MmpL4 and MmpS5/MmpL5
as siderophore export systems in Mtb and revealed that the MmpL proteins
transport small molecules other than lipids. MmpS4 and MmpS5 resemble
periplasmic adapter proteins of tripartite efflux pumps of Gram-negative
bacteria, however, they are not only required for export but also for efficient
siderophore synthesis. Membrane association of MbtG suggests a link between
siderophore synthesis and transport. The structure of the soluble domain of
MmpS4 (residues 52-140) was solved by NMR and indicates that mycobacterial MmpS
proteins constitute a novel class of transport accessory proteins. The bacterial
burden of the mmpS4/S5 deletion mutant in mouse lungs was lower by 10,000-fold
and none of the infected mice died within 180 days compared to wild-type Mtb.
This is the strongest attenuation observed so far for Mtb mutants lacking genes
involved in iron utilization. In conclusion, this study identified the first
components of novel siderophore export systems which are essential for virulence
of Mtb.
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