Identification of a Catalytic Exosite for Complement Component C4 on the Serine Protease Domain of C1s
(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:
https://lup.lub.lu.se/record/3147724
- author
- 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.
- organization
- publishing date
- 2012
- 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
- pmid:22855709
- 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
- 2016-04-01 13:08:57
- date last changed
- 2022-01-27 17:34:21
@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}}, doi = {{10.4049/jimmunol.1201085}}, volume = {{189}}, year = {{2012}}, }