|Bacterial Membranes - URA CNRS 2172|
|HEAD||Pr. WANDERSMAN Cécile / firstname.lastname@example.org|
|MEMBERS||BENEVIDES MATOS Najla/Dr BIVILLE Francis/BURGOS Monica/ /Dr CHESNEAU Olivier/ /Dr DASSA Elie/Dr DELEPELAIRE Philippe/DIAGNE Marième/FOURNIER Clémence Dr LETOFFE Sylvie/Dr NUNEZ SAMUDIO Virginia/PAQUELIN Annick/RAJARATNAM Thomas/THEPAUT Sylvana/WISZNIOWSKI Karine
Heme uptake and metabolism
Most organisms have a complete heme biosynthetic pathway. Nevertheless, exogenous heme is taken up by bacteria as an iron source. Exogenous free heme, or heme extracted from various hemoproteins, is internalized whole and degraded in the cytosol to retrieve iron. At the same time, free heme is highly toxic owing to the generation of reactive oxygen species. Thus, heme uptake and breakdown are usually highly regulated to maintain heme homeostasy
Over the last decade, the team has characterized the mechanisms of heme acquisition in gram negative bacteria : secretion of small proteins (hemophores) which bind heme with an extreme affinity and return it to outer membrane heme receptors ; mecanism of heme transfer from hemophores to heme receptors. The structure of the whole heme hemophore –receptor complex has recently been solved (1). The team has also studied the mechanism of heme transport through the inner membrane which can be achieve in Escherichia coli by two alternative permeases : a heme specific permease or a heme and dipeptide permease (2, 5) .
We are now starting the study of heme metabolism and have found a new pathway in E. coli allowing heme-iron extraction without breaking the tetrapyrrol ring. Orthologs are present in several gram positive species including Staphylococcus aureus and Mycobacterium tuberculosis.
Many proteins including hemophores are secreted by a transporter comprizing one ABC protein and two helper envelope proteins. The secretion signal usually located at the C-terminus interacts with the ABC protein, and modulates its ATPase activity. A hemophore mutant lacking its secretion signal is not secreted, but still interacts with the ABC protein and promotes a stable complex (4). We show that interaction involves multiple sites on the hemophore. The presence of these sites improve secretion allowing a « cotranslational secretion. The C terminus induces ATP hydrolysis and promotes the secretion protein complex dissociation. This model appears to be valid also for the E. coli a hemolysin .
ABC proteins lacking transmembrane domains
Studies on Upp (an ABC protein of unknown function) show that it acts on DNA to minimize transposon excision, a well-known example of illegitimate recombination. Vga(A), a Staphylococcus aureusABC protein of this family exhibits an ATPase activity inhibited by streptogramin but not by other antibiotics. Vga(A) could be involved in streptogramin efflux (3).MsrD a Streptococcus pneumoniaeortholog of VgaA is functional in E. coli and is currently studied.
Keywords: Membrane transport, iron acquisition, hemophore, ABC protein
1) Benevides-Matos N, Wandersman C, Biville F. 2008 HasB, the Serratia marcescens TonB paralog, is specific to HasR. J Bacteriol. 190 :21-27
2) Létoffé S, Delepelaire P, Wandersman C. 2008Functional differences between heme permeases: Serratia marcescens HemTUV permease exhibits a narrower substrate specificity (restricted to heme) than the Escherichia coli DppABCDF peptide-heme permease.J Bacteriol. 190:1866-1870
3) Jacquet E, Girard JM, Ramaen O, Pamlard O, Lévaique H, Betton JM, Dassa E, Chesneau O.2008ATP hydrolysis and pristinamycin IIA inhibition of the Staphylococcus aureus Vga(A), a dual ABC protein involved in streptogramin A resistance.J Biol Chem. 283 : 25332-25339.
4) Cescau S, Debarbieux L, Wandersman C. 2007Probing the in vivo dynamics of type I protein secretion complex association through sensitivity to detergents. J Bacteriol 189 1496-1504.
5) Létoffé S., DelepelaireP., Wandersman C. 2006The housekeeping dipeptide permease is the Escherichia coli heme transporter and functions with two optional peptide binding proteins.Proc Natl Acad Sci U S A. 103 12891-12896.
Activity Reports 2009 - Institut Pasteur
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