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Streptococcal M protein: Structural studies of the hypervariable region, free and bound to human C4BP

André, Ingemar LU ; Persson, J; Blom, AM; Nilsson, H; Drakenberg, Torbjörn LU ; Lindahl, Gunnar LU and Linse, Sara LU (2006) In Biochemistry 45(14). p.4559-4568
Abstract
Streptococcus pyogenes is a Gram-positive bacterium that causes several diseases, including acute tonsillitis and toxic shock syndrome. The surface-localized M protein, which is the most extensively studied virulence factor of S. pyogenes, has an similar to 50-residue N-terminal hypervariable region (HVR) that plays a key role in the escape of the host immunity. Despite the extensive sequence variability in this region, many HVRs specifically bind human C4b-binding protein (C4BP), a plasma protein that inhibits complement activation. Although the more conserved parts of M protein are known to have dimeric coiled-coil structure, it is unclear whether the HVR also is a coiled coil. Here, we use nuclear magnetic resonance (NMR) to study the... (More)
Streptococcus pyogenes is a Gram-positive bacterium that causes several diseases, including acute tonsillitis and toxic shock syndrome. The surface-localized M protein, which is the most extensively studied virulence factor of S. pyogenes, has an similar to 50-residue N-terminal hypervariable region (HVR) that plays a key role in the escape of the host immunity. Despite the extensive sequence variability in this region, many HVRs specifically bind human C4b-binding protein (C4BP), a plasma protein that inhibits complement activation. Although the more conserved parts of M protein are known to have dimeric coiled-coil structure, it is unclear whether the HVR also is a coiled coil. Here, we use nuclear magnetic resonance (NMR) to study the conformational properties of HVRs from M4 and M22 proteins in isolation and in complex with the M protein binding portion of C4BP. We conclude that the HVRs of M4 and M22 are folded as coiled coils and that the folded nucleus of the M4 HVR has a length of similar to 27 residues. Moreover, we demonstrate that the C4BP binding surface of M4-N is found within a region of four heptad repeats. Using molecular modeling, we propose a model for the structure of the M4 HVR that is consistent with our experimental information from NMR spectroscopy. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Biochemistry
volume
45
issue
14
pages
4559 - 4568
publisher
The American Chemical Society
external identifiers
  • wos:000236692100023
  • pmid:16584191
  • scopus:33645664015
ISSN
0006-2960
DOI
10.1021/bi052455c
language
English
LU publication?
yes
id
8f6bb1f2-92f9-4e30-b5f9-5cde94b5ce03 (old id 414650)
date added to LUP
2007-08-20 13:07:17
date last changed
2019-02-20 04:44:39
@article{8f6bb1f2-92f9-4e30-b5f9-5cde94b5ce03,
  abstract     = {Streptococcus pyogenes is a Gram-positive bacterium that causes several diseases, including acute tonsillitis and toxic shock syndrome. The surface-localized M protein, which is the most extensively studied virulence factor of S. pyogenes, has an similar to 50-residue N-terminal hypervariable region (HVR) that plays a key role in the escape of the host immunity. Despite the extensive sequence variability in this region, many HVRs specifically bind human C4b-binding protein (C4BP), a plasma protein that inhibits complement activation. Although the more conserved parts of M protein are known to have dimeric coiled-coil structure, it is unclear whether the HVR also is a coiled coil. Here, we use nuclear magnetic resonance (NMR) to study the conformational properties of HVRs from M4 and M22 proteins in isolation and in complex with the M protein binding portion of C4BP. We conclude that the HVRs of M4 and M22 are folded as coiled coils and that the folded nucleus of the M4 HVR has a length of similar to 27 residues. Moreover, we demonstrate that the C4BP binding surface of M4-N is found within a region of four heptad repeats. Using molecular modeling, we propose a model for the structure of the M4 HVR that is consistent with our experimental information from NMR spectroscopy.},
  author       = {André, Ingemar and Persson, J and Blom, AM and Nilsson, H and Drakenberg, Torbjörn and Lindahl, Gunnar and Linse, Sara},
  issn         = {0006-2960},
  language     = {eng},
  number       = {14},
  pages        = {4559--4568},
  publisher    = {The American Chemical Society},
  series       = {Biochemistry},
  title        = {Streptococcal M protein: Structural studies of the hypervariable region, free and bound to human C4BP},
  url          = {http://dx.doi.org/10.1021/bi052455c},
  volume       = {45},
  year         = {2006},
}