PUBLICATION
MATE transport of the E. coli-derived genotoxin colibactin
- Authors
- Mousa, J.J., Yang, Y., Tomkovich, S., Shima, A., Newsome, R.C., Tripathi, P., Oswald, E., Bruner, S.D., Jobin, C.
- ID
- ZDB-PUB-160831-8
- Date
- 2016
- Source
- Nature microbiology 1: 15009 (Journal)
- Registered Authors
- Keywords
- Bacterial genes, Transporters
- MeSH Terms
-
- Animals
- Crystallography, X-Ray
- DNA Damage/drug effects
- Disease Models, Animal
- Escherichia coli/metabolism*
- Escherichia coli Infections/microbiology
- Escherichia coli Infections/pathology
- Escherichia coli Proteins/chemistry
- Escherichia coli Proteins/metabolism*
- Ilex
- Mice
- Models, Molecular
- Mutagens/metabolism*
- Organic Cation Transport Proteins/chemistry
- Organic Cation Transport Proteins/metabolism*
- Peptides/metabolism*
- Polyketides/metabolism*
- Protein Conformation
- Protein Transport
- Zebrafish
- PubMed
- 27571755 Full text @ Nat Microbiol
Citation
Mousa, J.J., Yang, Y., Tomkovich, S., Shima, A., Newsome, R.C., Tripathi, P., Oswald, E., Bruner, S.D., Jobin, C. (2016) MATE transport of the E. coli-derived genotoxin colibactin. Nature microbiology. 1:15009.
Abstract
Various forms of cancer have been linked to the carcinogenic activities of microorganisms(1-3). The virulent gene island polyketide synthase (pks) produces the secondary metabolite colibactin, a genotoxic molecule(s) causing double-stranded DNA breaks(4) and enhanced colorectal cancer development(5,6). Colibactin biosynthesis involves a prodrug resistance strategy where an N-terminal prodrug scaffold (precolibactin) is assembled, transported into the periplasm and cleaved to release the mature product(7-10). Here, we show that ClbM, a multidrug and toxic compound extrusion (MATE) transporter, is a key component involved in colibactin activity and transport. Disruption of clbM attenuated pks+ E. coli-induced DNA damage in vitro and significantly decreased the DNA damage response in gnotobiotic Il10(-/-) mice. Colonization experiments performed in mice or zebrafish animal models indicate that clbM is not implicated in E. coli niche establishment. The X-ray structure of ClbM shows a structural motif common to the recently described MATE family. The 12-transmembrane ClbM is characterized as a cation-coupled antiporter, and residues important to the cation-binding site are identified. Our data identify ClbM as a precolibactin transporter and provide the first structure of a MATE transporter with a defined and specific biological function.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping