Abstract
Many pathogenic microorganisms evade host immunity through extensive sequence variability in a protein region targeted by protective antibodies. In spite of the sequence variability, a variable region commonly retains an important ligand-binding function, reflected in the presence of a highly conserved sequence motif. Here, we analyze the limits of sequence divergence in a ligand-binding region by characterizing the hypervariable region (HVR) of Streptococcus pyogenes M protein. Our studies were focused on HVRs that bind the human complement regulator C4b-binding protein (C4BP), a ligand that confers phagocytosis resistance. A previous comparison of C4BP-binding HVRs identified residue identities that could be part of a binding motif, but the extended analysis reported here shows that no residue identities remain when additional C4BP-binding HVRs are included. Characterization of the HVR in the M22 protein indicated that two relatively conserved Leu residues are essential for C4BP binding, but these residues are probably core residues in a coiled-coil, implying that they do not directly contribute to binding. In contrast, substitution of either of two relatively conserved Glu residues, predicted to be solvent-exposed, had no effect on C4BP binding, although each of these changes had a major effect on the antigenic properties of the HVR. Together, these findings show that HVRs of M proteins have an extraordinary capacity for sequence divergence and antigenic variability while retaining a specific ligand-binding function.
Highlights
Sequence variability is a common feature in surface proteins of pathogenic microorganisms
The three identities correspond to L28, E31, and D40 in M22, an extensively studied C4BPbinding M protein which we used as model protein [18,20,21,24]
In many strains of S. pyogenes, the binding of human C4bbinding protein (C4BP) to M protein plays an important role for the ability of the bacteria to evade phagocytosis [20,21]
Summary
Sequence variability is a common feature in surface proteins of pathogenic microorganisms. The sequence variability that gives rise to antigenic variation may be very extensive and represents an apparent paradox because the variable protein must retain an important function in spite of the variability. To explain this apparent contradiction, it is commonly assumed that conservation of a limited number of residues is sufficient to promote correct protein folding and/or to confer a specific function [7], while other residues may vary and cause changes in antigenic properties of the protein. We show here that the hypervariable region (HVR) in streptococcal M protein, a major bacterial virulence factor, retains ability to bind a human protein ligand, different HVRs completely lack residue identities
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
