title: Structure-function mapping of BbCRASP-1, the key complement factor H and FHL-1 binding protein of Borrelia burgdorferi.
abstract: Borrelia burgdorferi, a spirochaete transmitted to human hosts during feeding of infected Ixodes ticks, is the causative agent of Lyme disease, the most frequent vector-borne disease in Eurasia and North America. Sporadically Lyme disease develops into a chronic, multisystemic disorder. Serum-resistant B. burgdorferi strains bind complement factor H (FH) and FH-like protein 1 (FHL-1) on the spirochaete surface. This binding is dependent on the expression of proteins termed complement-regulator acquiring surface proteins (CRASPs). The atomic structure of BbCRASP-1, the key FHL-1/FH-binding protein of B. burgdorferi, has recently been determined. Our analysis indicates that its protein topology apparently evolved to provide a high affinity interaction site for FH/FHL-1 and leads to an atomic-level hypothesis for the functioning of BbCRASP-1. This work demonstrates that pathogens interact with complement regulators in ways that are distinct from the mechanisms used by the host and are thus obvious targets for drug design.
authors.affiliation: Laboratory of Molecular Biophysics, Department of Biochemistry, University of Oxford, South Parks Road, Oxford OX1 3QU, UK.
authors.forename: Frank S
authors.initials: FS
authors.lastname: Cordes
authors.forename: Peter
authors.initials: P
authors.lastname: Kraiczy
authors.forename: Pietro
authors.initials: P
authors.lastname: Roversi
authors.forename: Markus M
authors.initials: MM
authors.lastname: Simon
authors.forename: Volker
authors.initials: V
authors.lastname: Brade
authors.forename: Oliver
authors.initials: O
authors.lastname: Jahraus
authors.forename: Russell
authors.initials: R
authors.lastname: Wallis
authors.forename: Leo
authors.initials: L
authors.lastname: Goodstadt
authors.forename: Chris P
authors.initials: CP
authors.lastname: Ponting
authors.forename: Christine
authors.initials: C
authors.lastname: Skerka
authors.forename: Peter F
authors.initials: PF
authors.lastname: Zipfel
authors.forename: Reinhard
authors.initials: R
authors.lastname: Wallich
authors.forename: Susan M
authors.initials: SM
authors.lastname: Lea
mesh_terms: D000595:Amino Acid Sequence; D001426:Bacterial Proteins / Q000737:chemistry*; D001665:Binding Sites; D025065:Borrelia burgdorferi / Q000737:chemistry*; D003180:Complement C3b Inactivator Proteins; D017242:Complement Factor H / Q000378:metabolism; D006801:Humans; D008565:Membrane Proteins / Q000737:chemistry*; D008958:Models, Molecular; D008969:Molecular Sequence Data; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D016415:Sequence Alignment; D013329:Structure-Activity Relationship
chemical_list: D001426:Bacterial Proteins; C517621:CFHR1 protein, human; D003180:Complement C3b Inactivator Proteins; D008565:Membrane Proteins; C440651:complement regulator-acquiring surface proteins, Borrelia burgdorferi; D017242:Complement Factor H