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The modular architecture of meningococcal factor H-binding protein

Center for Immunobiology and Vaccine Development, Children's Hospital Oakland Research Institute, Oakland, CA 94609, USA

Meningococcal factor H binding protein (fHbp) is a promising vaccine antigen that binds the human complement downregulatory molecule factor H (fH), and this binding enhances the survival of the organism in serum. Based on sequence variability of the entire protein, fHbp has been divided into three variant groups or two subfamilies. Here, we present evidence based on phylogenetic analysis of 70 unique fHbp amino acid sequences that the molecular architecture is modular. From sequences of natural chimeras we identified blocks of two to five invariant residues that flanked five modular variable segments. Although overall, 46 % of the fHbp amino acids were invariant, based on a crystal structure, the invariant blocks that flanked the modular variable segments clustered on the membrane surface containing the amino-terminal lipid anchor, while the remaining invariant residues were located throughout the protein. Each of the five modular variable segments could be classified into one of two types, designated or β, based on homology with segments encoded by variant 1 or 3 fHbp genes, respectively. Forty of the fHbps (57 %) comprised only (n=33) or β (n=7) type segments. The remaining 30 proteins (43 %) were chimeras and could be classified into one of four modular groups. These included all 15 proteins assigned to the previously described variant 2 in subfamily A. The modular segments of one chimeric modular group had 96 % amino acid identity with those of fHbp orthologs in Neisseria gonorrhoeae. Collectively, the data suggest that recombination between Neisseria meningitidis and N. gonorrhoeae progenitors generated a family of modular, antigenically diverse meningococcal fHbps.

Correspondence
Dan M. Granoff
dgranoff{at}chori.org

Four supplementary tables (with supplementary references), listing source strains and characteristics of unique fHbp variants sorted by modular group, parameters used for phylogenetic analyses, distribution of fHbp variants in each clonal complex, and unique sequences in fHbp variable segments and numbers from each variant group, and a supplementary figure, showing the mean number of peptides and percentage amino acid identity for each of the five modular variable segments, are available with the online version of this paper.