Abstract
Factor H-binding protein is a 27-kDa lipoprotein of Neisseria meningitidis discovered while screening the bacterial genome for vaccine candidates. In addition to being an important component of a vaccine against meningococcus in late stage of development, the protein is essential for pathogenesis because it allows the bacterium to survive and grow in human blood by binding the human complement factor H. We recently reported the solution structure of the C-terminal domain of factor H-binding protein, which contains the immunodominant epitopes. In the present study, we report the structure of the full-length molecule, determined by nuclear magnetic resonance spectroscopy. The protein is composed of two independent barrels connected by a short link. Mapping the residues recognized by monoclonal antibodies with bactericidal or factor H binding inhibition properties allowed us to predict the sites involved in the function of the protein. The structure therefore provides the basis for designing improved vaccine molecules.
Highlights
Neisseria meningitidis, a Gram-negative bacterium that colonizes the upper respiratory tract of 10% of healthy human population, is adapted to grow only in humans
New perspectives to meningococcal B prevention have been opened by the identification of suitable protein-based vaccine antigens identified by mining the bacterial genome [4]
We determined the structure of the full-length factor H-binding protein (fHbp) by NMR, which improves the knowledge about the distribution of protective epitopes on the protein surface and provides useful indications on the possible localization of the factor H binding site
Summary
Solution Structure of the Factor H-binding Protein, a Survival Factor and Protective Antigen of Neisseria meningitidis*□S. The molecular distribution of residues from 141 to 255 was appreciable onto the structure of C terminus domain, whose solution structure was already solved [12], spatial arrangement of Gly-121 and Lys-122 remained so far undetermined This incompleteness of information hampered a detailed evaluation of the molecular distribution of variant-specific epitopes, as well as the opportunity to rationalize the reported differences in the ability of monoclonals to induce complement-mediated killing and inhibit the protein binding to human factor H [11]. We determined the structure of the full-length fHbp by NMR, which improves the knowledge about the distribution of protective epitopes on the protein surface and provides useful indications on the possible localization of the factor H (fH) binding site
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