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Extreme sequence divergence but conserved ligand-binding specificity in Streptococcus pyogenes M protein.

Persson, Jenny J LU ; Beall, Bernard ; Linse, Sara LU and Lindahl, Gunnar LU (2006) In PLoS Pathogens 2(5). p.442-452
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... (More)
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. (Less)
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organization
publishing date
type
Contribution to journal
publication status
published
subject
in
PLoS Pathogens
volume
2
issue
5
pages
442 - 452
publisher
Public Library of Science
external identifiers
  • wos:000202894500011
  • scopus:33646923133
ISSN
1553-7366
DOI
10.1371/journal.ppat.0020047
language
English
LU publication?
yes
id
2f4b71ba-270e-4e9f-8057-67fb1626296e (old id 156497)
date added to LUP
2016-04-01 11:44:16
date last changed
2021-05-25 02:26:51
@article{2f4b71ba-270e-4e9f-8057-67fb1626296e,
  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.},
  author       = {Persson, Jenny J and Beall, Bernard and Linse, Sara and Lindahl, Gunnar},
  issn         = {1553-7366},
  language     = {eng},
  number       = {5},
  pages        = {442--452},
  publisher    = {Public Library of Science},
  series       = {PLoS Pathogens},
  title        = {Extreme sequence divergence but conserved ligand-binding specificity in Streptococcus pyogenes M protein.},
  url          = {https://lup.lub.lu.se/search/files/2618591/625454.pdf},
  doi          = {10.1371/journal.ppat.0020047},
  volume       = {2},
  year         = {2006},
}