title: Solution structure of CCP modules 10-12 illuminates functional architecture of the complement regulator, factor H.
abstract: The 155-kDa plasma glycoprotein factor H (FH), which consists of 20 complement control protein (CCP) modules, protects self-tissue but not foreign organisms from damage by the complement cascade. Protection is achieved by selective engagement of FH, via CCPs 1-4, CCPs 6-8 and CCPs 19-20, with polyanion-rich host surfaces that bear covalently attached, activation-specific, fragments of complement component C3. The role of intervening CCPs 9-18 in this process is obscured by lack of structural knowledge. We have concatenated new high-resolution solution structures of overlapping recombinant CCP pairs, 10-11 and 11-12, to form a three-dimensional structure of CCPs 10-12 and validated it by small-angle X-ray scattering of the recombinant triple-module fragment. Superimposing CCP 12 of this 10-12 structure with CCP 12 from the previously solved CCP 12-13 structure yielded an S-shaped structure for CCPs 10-13 in which modules are tilted by 80-110° with respect to immediate neighbors, but the bend between CCPs 10 and 11 is counter to the arc traced by CCPs 11-13. Including this four-CCP structure in interpretation of scattering data for the longer recombinant segments, CCPs 10-15 and 8-15, implied flexible attachment of CCPs 8 and 9 to CCP 10 but compact and intimate arrangements of CCP 14 with CCPs 12, 13 and 15. Taken together with difficulties in recombinant production of module pairs 13-14 and 14-15, the aberrant structure of CCP 13 and the variability of 13-14 linker sequences among orthologues, a structural dependency of CCP 14 on its neighbors is suggested; this has implications for the FH mechanism.
authors.affiliation: Schools of Chemistry and Biological Sciences, University of Edinburgh, Edinburgh EH9 3JJ, UK.
authors.forename: Elisavet
authors.initials: E
authors.lastname: Makou
authors.forename: Haydyn D T
authors.initials: HD
authors.lastname: Mertens
authors.forename: Mateusz
authors.initials: M
authors.lastname: Maciejewski
authors.forename: Dinesh C
authors.initials: DC
authors.lastname: Soares
authors.forename: Ilias
authors.initials: I
authors.lastname: Matis
authors.forename: Christoph Q
authors.initials: CQ
authors.lastname: Schmidt
authors.forename: Andrew P
authors.initials: AP
authors.lastname: Herbert
authors.forename: Dmitri I
authors.initials: DI
authors.lastname: Svergun
authors.forename: Paul N
authors.initials: PN
authors.lastname: Barlow
mesh_terms: D017242:Complement Factor H / Q000737:chemistry* / Q000378:metabolism*; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D011487:Protein Conformation
chemical_list: D017242:Complement Factor H