title: An internal thioester in a pathogen surface protein mediates covalent host binding.
abstract: To cause disease and persist in a host, pathogenic and commensal microbes must adhere to tissues. Colonization and infection depend on specific molecular interactions at the host-microbe interface that involve microbial surface proteins, or adhesins. To date, adhesins are only known to bind to host receptors non-covalently. Here we show that the streptococcal surface protein SfbI mediates covalent interaction with the host protein fibrinogen using an unusual internal thioester bond as a 'chemical harpoon'. This cross-linking reaction allows bacterial attachment to fibrin and SfbI binding to human cells in a model of inflammation. Thioester-containing domains are unexpectedly prevalent in Gram-positive bacteria, including many clinically relevant pathogens. Our findings support bacterial-encoded covalent binding as a new molecular principle in host-microbe interactions. This represents an as yet unexploited target to treat bacterial infection and may also offer novel opportunities for engineering beneficial interactions.
authors.affiliation: Department of Biological Chemistry, John Innes Centre, Norwich, United Kingdom.
authors.forename: Miriam
authors.initials: M
authors.lastname: Walden
authors.affiliation: Biomedical Sciences Research Complex, University of St Andrews, St Andrews, United Kingdom.
authors.forename: John M
authors.initials: JM
authors.lastname: Edwards
authors.affiliation: Biomedical Sciences Research Complex, University of St Andrews, St Andrews, United Kingdom.
authors.forename: Aleksandra M
authors.initials: AM
authors.lastname: Dziewulska
authors.affiliation: Central Facility for Microscopy, Helmholtz Centre for Infection Research, Braunschweig, Germany.
authors.forename: Rene
authors.initials: R
authors.lastname: Bergmann
authors.affiliation: Department of Biological Chemistry, John Innes Centre, Norwich, United Kingdom.
authors.forename: Gerhard
authors.initials: G
authors.lastname: Saalbach
authors.affiliation: Biomedical Sciences Research Complex, University of St Andrews, St Andrews, United Kingdom.
authors.forename: Su-Yin
authors.initials: SY
authors.lastname: Kan
authors.affiliation: Biomedical Sciences Research Complex, University of St Andrews, St Andrews, United Kingdom.
authors.forename: Ona K
authors.initials: OK
authors.lastname: Miller
authors.affiliation: Biomedical Sciences Research Complex, University of St Andrews, St Andrews, United Kingdom.
authors.forename: Miriam
authors.initials: M
authors.lastname: Weckener
authors.affiliation: Biomedical Sciences Research Complex, University of St Andrews, St Andrews, United Kingdom.
authors.forename: Rosemary J
authors.initials: RJ
authors.lastname: Jackson
authors.affiliation: Biomedical Sciences Research Complex, University of St Andrews, St Andrews, United Kingdom.
authors.forename: Sally L
authors.initials: SL
authors.lastname: Shirran
authors.affiliation: Biomedical Sciences Research Complex, University of St Andrews, St Andrews, United Kingdom.
authors.forename: Catherine H
authors.initials: CH
authors.lastname: Botting
authors.affiliation: Biomedical Sciences Research Complex, University of St Andrews, St Andrews, United Kingdom.
authors.forename: Gordon J
authors.initials: GJ
authors.lastname: Florence
authors.affiliation: Central Facility for Microscopy, Helmholtz Centre for Infection Research, Braunschweig, Germany.
authors.forename: Manfred
authors.initials: M
authors.lastname: Rohde
authors.affiliation: Department of Biological Chemistry, John Innes Centre, Norwich, United Kingdom.
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Banfield
authors.affiliation: Biomedical Sciences Research Complex, University of St Andrews, St Andrews, United Kingdom.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Schwarz-Linek
mesh_terms: D018829:Adhesins, Bacterial / Q000378:metabolism*; D002352:Carrier Proteins / Q000378:metabolism*; D004926:Escherichia coli / Q000201:enzymology; D005337:Fibrin / Q000378:metabolism; D005340:Fibrinogen / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000378:metabolism* / Q000382:microbiology; D008565:Membrane Proteins / Q000378:metabolism*
chemical_list: D018829:Adhesins, Bacterial; D002352:Carrier Proteins; D008565:Membrane Proteins; C078635:fibronectin-binding proteins, bacterial; D005337:Fibrin; D005340:Fibrinogen
keywords: Clostridium perfringens; Streptococcus pneumoniae; Streptococcus pyogenes; bacterial surface proteins; biophysics; fibrinogen; host-microbe interactions; infectious disease; microbiology; structural biology