Advanced

Identification of a Catalytic Exosite for Complement Component C4 on the Serine Protease Domain of C1s

Duncan, Renee C.; Mohlin, Frida LU ; Taleski, Deni; Coetzer, Theresa H.; Huntington, James A.; Payne, Richard J.; Blom, Anna LU ; Pike, Robert N. and Wijeyewickrema, Lakshmi C. (2012) In Journal of Immunology 189(5). p.2365-2373
Abstract
The classical pathway of complement is crucial to the immune system, but it also contributes to inflammatory diseases when dys-regulated. Binding of the C1 complex to ligands activates the pathway by inducing autoactivation of associated C1r, after which C1r activates C1s. C1s cleaves complement component C4 and then C2 to cause full activation of the system. The interaction between C1s and C4 involves active site and exosite-mediated events, but the molecular details are unknown. In this study, we identified four positively charged amino acids on the serine protease domain that appear to form a catalytic exosite that is required for efficient cleavage of C4. These residues are coincidentally involved in coordinating a sulfate ion in the... (More)
The classical pathway of complement is crucial to the immune system, but it also contributes to inflammatory diseases when dys-regulated. Binding of the C1 complex to ligands activates the pathway by inducing autoactivation of associated C1r, after which C1r activates C1s. C1s cleaves complement component C4 and then C2 to cause full activation of the system. The interaction between C1s and C4 involves active site and exosite-mediated events, but the molecular details are unknown. In this study, we identified four positively charged amino acids on the serine protease domain that appear to form a catalytic exosite that is required for efficient cleavage of C4. These residues are coincidentally involved in coordinating a sulfate ion in the crystal structure of the protease. Together with other evidence, this pointed to the involvement of sulfate ions in the interaction with the C4 substrate, and we showed that the protease interacts with a peptide from C4 containing three sulfotyrosine residues. We present a molecular model for the interaction between C1s and C4 that provides support for the above data and poses questions for future research into this aspect of complement activation. The Journal of Immunology, 2012, 189: 2365-2373. (Less)
Please use this url to cite or link to this publication:
author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Journal of Immunology
volume
189
issue
5
pages
2365 - 2373
publisher
American Association of Immunologists
external identifiers
  • wos:000308083600036
  • scopus:84865419895
ISSN
1550-6606
DOI
10.4049/jimmunol.1201085
language
English
LU publication?
yes
id
5e45aacd-6fd8-4aaf-aa4e-c2085022609a (old id 3147724)
date added to LUP
2012-11-01 09:33:09
date last changed
2017-06-25 03:52:21
@article{5e45aacd-6fd8-4aaf-aa4e-c2085022609a,
  abstract     = {The classical pathway of complement is crucial to the immune system, but it also contributes to inflammatory diseases when dys-regulated. Binding of the C1 complex to ligands activates the pathway by inducing autoactivation of associated C1r, after which C1r activates C1s. C1s cleaves complement component C4 and then C2 to cause full activation of the system. The interaction between C1s and C4 involves active site and exosite-mediated events, but the molecular details are unknown. In this study, we identified four positively charged amino acids on the serine protease domain that appear to form a catalytic exosite that is required for efficient cleavage of C4. These residues are coincidentally involved in coordinating a sulfate ion in the crystal structure of the protease. Together with other evidence, this pointed to the involvement of sulfate ions in the interaction with the C4 substrate, and we showed that the protease interacts with a peptide from C4 containing three sulfotyrosine residues. We present a molecular model for the interaction between C1s and C4 that provides support for the above data and poses questions for future research into this aspect of complement activation. The Journal of Immunology, 2012, 189: 2365-2373.},
  author       = {Duncan, Renee C. and Mohlin, Frida and Taleski, Deni and Coetzer, Theresa H. and Huntington, James A. and Payne, Richard J. and Blom, Anna and Pike, Robert N. and Wijeyewickrema, Lakshmi C.},
  issn         = {1550-6606},
  language     = {eng},
  number       = {5},
  pages        = {2365--2373},
  publisher    = {American Association of Immunologists},
  series       = {Journal of Immunology},
  title        = {Identification of a Catalytic Exosite for Complement Component C4 on the Serine Protease Domain of C1s},
  url          = {http://dx.doi.org/10.4049/jimmunol.1201085},
  volume       = {189},
  year         = {2012},
}