Solution Structure of the Immunodominant Domain of Protective Antigen GNA1870 of Neisseria meningitidis

Francesca Cantini,Silvana Savino,Maria Scarselli,Vega Masignani,Mariagrazia Pizza,Giacomo Romagnoli,Erwin Swennen,Daniele Veggi,Lucia Banci,Rino Rappuoli

doi:10.1074/jbc.m508595200

Abstract

GNA1870, a 28-kDa surface-exposed lipoprotein of Neisseria meningitidis recently discovered by reverse vaccinology, is one of the most potent antigens of Meningococcus and a promising candidate for a universal vaccine against a devastating disease. Previous studies of epitope mapping and genetic characterization identified residues critical for bactericidal response within the C-terminal domain of the molecule. To elucidate the conformation of protective epitopes, we used NMR spectroscopy to obtain the solution structure of the immunodominant 18-kDa C-terminal portion of GNA1870. The structure consists of an eight-stranded antiparallel beta-barrel overlaid by a short alpha-helix with an unstructured N-terminal end. Residues previously shown to be important for antibody recognition were mapped on loops facing the same ridge of the molecule. The sequence similarity of GNA1870 with members of the bacterial transferrin receptor family allows one to predict the folding of this class of well known bacterial antigens, providing the basis for the rational engineering of high affinity B cell epitopes.

Highlights

Three-dimensional structures of two neisserial antigens, NspA [11] and OpcA [12], have been solved, both showing a very similar architecture
genome-derived Neisseria antigen 1870 (GNA1870), a 28-kDa surface-exposed lipoprotein of Neisseria meningitidis recently discovered by reverse vaccinology, is one of the most potent antigens of Meningococcus and a promising candidate for a universal vaccine against a devastating disease
Genome-derived Neisseria antigen 1870 (GNA1870)2 is a lipoprotein of unknown function that shares a weak sequence similarity to the B component of transferrin receptor produced by the pathogenic bacteria of Neisseriaceae and Pasteurellaceae [13]

Summary

Introduction

Three-dimensional structures of two neisserial antigens, NspA [11] and OpcA [12], have been solved, both showing a very similar architecture They are outer membrane proteins constituted by a variable number of antiparallel ␤-strands connected by periplasm-faced and surfaceexposed mobile loops that bear the epitopes responsible for bactericidal activity. Reverse vaccinology was exploited for the identification of novel surface-exposed protein antigens to be used in a vaccine formulation against Meningococcus B. By this approach, several potential vaccine candidates were recognized, some of which are presently undergoing clinical trials. Independent studies have identified the sequence Glu146-Arg149 as part of a bactericidal epitope [20]

Methods

Results

Conclusion