The modular architecture of meningococcal factor H-binding protein

Area of Science:

• Microbiology
• Immunology
• Structural Biology

Background:

• Meningococcal factor H binding protein (fHbp) is a key virulence factor and vaccine candidate.
• fHbp facilitates Neisseria meningitidis survival by binding human factor H, inhibiting complement.
• Existing classification divides fHbp into three variants/two subfamilies based on sequence variability.

Purpose of the Study:

• To investigate the molecular architecture of fHbp using phylogenetic analysis.
• To identify conserved and variable regions within fHbp.
• To understand the evolutionary origins of fHbp diversity.

Main Methods:

• Phylogenetic analysis of 70 unique fHbp amino acid sequences.
• Identification of conserved residue blocks and modular variable segments.
• Comparison with crystal structure data and orthologs in Neisseria gonorrhoeae.

Main Results:

• fHbp possesses a modular structure with five variable segments flanked by invariant residue blocks.
• Invariant blocks are primarily located on the membrane-proximal surface.
• Variable segments are of two types (alpha/beta), with many fHbps being chimeras, including variant 2.
• One chimeric group shows high homology to Neisseria gonorrhoeae fHbps.

Conclusions:

• fHbp's modular architecture suggests a mosaic evolutionary history.
• Recombination between Neisseria meningitidis and Neisseria gonorrhoeae likely generated fHbp diversity.
• Understanding this modularity is crucial for developing broadly protective meningococcal vaccines.