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Binding of human C4BP to the hypervariable region of M protein: a molecular mechanism of phagocytosis resistance in Streptococcus pyogenes

Berggård, Karin LU ; Johnsson, E.; Morfeldt, E.; Persson, J.; Stålhammar-Carlemalm, Margaretha LU and Lindahl, G. (2001) In Molecular Microbiology 42(2). p.539-551
Abstract
The amino-terminal hypervariable region (HVR) of streptococcal M protein is required for the ability of this virulence factor to confer phagocytosis resistance. The function of the HVR has remained unknown, but the finding that many HVRs with extremely divergent sequences bind the human complement regulator C4b-binding protein (C4BP) has suggested that this ligand may play a role in phagocytosis resistance. We used the M22 system to study the function of bound C4BP and provide several lines of evidence that C4BP indeed contributes to phagocytosis resistance. First, the ability of anti-HVR antibodies to cause opsonization correlated with their ability to inhibit binding of C4BP. Secondly, a short deletion in the HVR eliminated C4BP binding... (More)
The amino-terminal hypervariable region (HVR) of streptococcal M protein is required for the ability of this virulence factor to confer phagocytosis resistance. The function of the HVR has remained unknown, but the finding that many HVRs with extremely divergent sequences bind the human complement regulator C4b-binding protein (C4BP) has suggested that this ligand may play a role in phagocytosis resistance. We used the M22 system to study the function of bound C4BP and provide several lines of evidence that C4BP indeed contributes to phagocytosis resistance. First, the ability of anti-HVR antibodies to cause opsonization correlated with their ability to inhibit binding of C4BP. Secondly, a short deletion in the HVR eliminated C4BP binding and also reduced the ability of M22 to confer phagocytosis resistance. Thirdly, the addition of an excess of pure C4BP to a phagocytosis system almost completely blocked the effect of opsonizing anti-HVR antibodies. Together, our data indicate that binding of C4BP to the HVR of M22 plays an important role in phagocytosis resistance, but other properties of M22 also contribute. This study provides the first molecular insight into the mechanisms by which the HVR of an M protein confers phagocytosis resistance. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Molecular Microbiology
volume
42
issue
2
pages
539 - 551
publisher
Wiley-Blackwell
external identifiers
  • wos:000172098700021
  • scopus:0034768706
ISSN
1365-2958
language
English
LU publication?
yes
id
07425b9a-6b9c-4293-b0a7-a5279d162aaa (old id 1118690)
date added to LUP
2008-06-24 14:11:56
date last changed
2018-05-29 09:25:20
@article{07425b9a-6b9c-4293-b0a7-a5279d162aaa,
  abstract     = {The amino-terminal hypervariable region (HVR) of streptococcal M protein is required for the ability of this virulence factor to confer phagocytosis resistance. The function of the HVR has remained unknown, but the finding that many HVRs with extremely divergent sequences bind the human complement regulator C4b-binding protein (C4BP) has suggested that this ligand may play a role in phagocytosis resistance. We used the M22 system to study the function of bound C4BP and provide several lines of evidence that C4BP indeed contributes to phagocytosis resistance. First, the ability of anti-HVR antibodies to cause opsonization correlated with their ability to inhibit binding of C4BP. Secondly, a short deletion in the HVR eliminated C4BP binding and also reduced the ability of M22 to confer phagocytosis resistance. Thirdly, the addition of an excess of pure C4BP to a phagocytosis system almost completely blocked the effect of opsonizing anti-HVR antibodies. Together, our data indicate that binding of C4BP to the HVR of M22 plays an important role in phagocytosis resistance, but other properties of M22 also contribute. This study provides the first molecular insight into the mechanisms by which the HVR of an M protein confers phagocytosis resistance.},
  author       = {Berggård, Karin and Johnsson, E. and Morfeldt, E. and Persson, J. and Stålhammar-Carlemalm, Margaretha and Lindahl, G.},
  issn         = {1365-2958},
  language     = {eng},
  number       = {2},
  pages        = {539--551},
  publisher    = {Wiley-Blackwell},
  series       = {Molecular Microbiology},
  title        = {Binding of human C4BP to the hypervariable region of M protein: a molecular mechanism of phagocytosis resistance in Streptococcus pyogenes},
  volume       = {42},
  year         = {2001},
}