title: MATE transport of the E. coli-derived genotoxin colibactin.
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.
authors: Department of Chemistry, University of Florida, Gainesville, Florida 32611, USA.
authors: Jarrod J
authors: JJ
authors: Mousa
authors: Department of Medicine, University of Florida, Gainesville, Florida 32611, USA.
authors: Ye
authors: Y
authors: Yang
authors: Department of Medicine, University of Florida, Gainesville, Florida 32611, USA.
authors: Sarah
authors: S
authors: Tomkovich
authors: INRA, USC 1360, F-31300 Toulouse, France.|Inserm, UMR1043, F-31300 Toulouse, France.|CNRS, UMR5282, F-31400 Toulouse, France.|Université de Toulouse, UPS, Centre de Physiopathologie de Toulouse Purpan (CPTP), F-31400 Toulouse, France.|CHU Toulouse, Hôpital Purpan, Service de bactériologie-Hygiène, F-31059 Toulouse, France.
authors: Ayaka
authors: A
authors: Shima
authors: Department of Chemistry, University of Florida, Gainesville, Florida 32611, USA.
authors: Rachel C
authors: RC
authors: Newsome
authors: Department of Chemistry, University of Florida, Gainesville, Florida 32611, USA.
authors: Prabhanshu
authors: P
authors: Tripathi
authors: INRA, USC 1360, F-31300 Toulouse, France.|Inserm, UMR1043, F-31300 Toulouse, France.|CNRS, UMR5282, F-31400 Toulouse, France.|Université de Toulouse, UPS, Centre de Physiopathologie de Toulouse Purpan (CPTP), F-31400 Toulouse, France.|CHU Toulouse, Hôpital Purpan, Service de bactériologie-Hygiène, F-31059 Toulouse, France.
authors: Eric
authors: E
authors: Oswald
authors: Department of Chemistry, University of Florida, Gainesville, Florida 32611, USA.
authors: Steven D
authors: SD
authors: Bruner
authors: Department of Medicine, University of Florida, Gainesville, Florida 32611, USA.|Department of Infectious Diseases and Pathology, University of Florida, Gainesville, Florida 32611, USA.
authors: Christian
authors: C
authors: Jobin
mesh_terms: D000818:Animals; D018360:Crystallography, X-Ray; D004249:DNA Damage / Q000187:drug effects; D004195:Disease Models, Animal; D004926:Escherichia coli / Q000378:metabolism*; D004927:Escherichia coli Infections / Q000382:microbiology / Q000473:pathology; D029968:Escherichia coli Proteins / Q000737:chemistry / Q000378:metabolism*; D030017:Ilex; D051379:Mice; D008958:Models, Molecular; D009153:Mutagens / Q000378:metabolism*; D027701:Organic Cation Transport Proteins / Q000737:chemistry / Q000378:metabolism*; D010455:Peptides / Q000378:metabolism*; D061065:Polyketides / Q000378:metabolism*; D011487:Protein Conformation; D021381:Protein Transport; D015027:Zebrafish
chemical_list: C000619950:ClbM protein, E coli; D029968:Escherichia coli Proteins; D009153:Mutagens; D027701:Organic Cation Transport Proteins; D010455:Peptides; D061065:Polyketides; C569566:colibactin