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Structural basis for activation of the complement system by component C4 cleavage

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Standard

Structural basis for activation of the complement system by component C4 cleavage. / Kidmose, Rune T; Laursen, Nick S; Dobó, József; Kjaer, Troels R; Sirotkina, Sofia; Yatime, Laure; Sottrup-Jensen, Lars; Thiel, Steffen; Gál, Péter; Andersen, Gregers Rom.

I: Proceedings of the National Academy of Sciences of the United States of America, Bind 109, Nr. 38, 18.09.2012, s. 15425-15430.

Publikation: Bidrag til tidsskrift/Konferencebidrag i tidsskrift /Bidrag til avisTidsskriftartikelForskningpeer review

Harvard

Kidmose, RT, Laursen, NS, Dobó, J, Kjaer, TR, Sirotkina, S, Yatime, L, Sottrup-Jensen, L, Thiel, S, Gál, P & Andersen, GR 2012, 'Structural basis for activation of the complement system by component C4 cleavage', Proceedings of the National Academy of Sciences of the United States of America, bind 109, nr. 38, s. 15425-15430. https://doi.org/10.1073/pnas.1208031109

APA

Kidmose, R. T., Laursen, N. S., Dobó, J., Kjaer, T. R., Sirotkina, S., Yatime, L., Sottrup-Jensen, L., Thiel, S., Gál, P., & Andersen, G. R. (2012). Structural basis for activation of the complement system by component C4 cleavage. Proceedings of the National Academy of Sciences of the United States of America, 109(38), 15425-15430. https://doi.org/10.1073/pnas.1208031109

CBE

Kidmose RT, Laursen NS, Dobó J, Kjaer TR, Sirotkina S, Yatime L, Sottrup-Jensen L, Thiel S, Gál P, Andersen GR. 2012. Structural basis for activation of the complement system by component C4 cleavage. Proceedings of the National Academy of Sciences of the United States of America. 109(38):15425-15430. https://doi.org/10.1073/pnas.1208031109

MLA

Kidmose, Rune T o.a.. "Structural basis for activation of the complement system by component C4 cleavage". Proceedings of the National Academy of Sciences of the United States of America. 2012, 109(38). 15425-15430. https://doi.org/10.1073/pnas.1208031109

Vancouver

Kidmose RT, Laursen NS, Dobó J, Kjaer TR, Sirotkina S, Yatime L o.a. Structural basis for activation of the complement system by component C4 cleavage. Proceedings of the National Academy of Sciences of the United States of America. 2012 sep 18;109(38):15425-15430. https://doi.org/10.1073/pnas.1208031109

Author

Kidmose, Rune T ; Laursen, Nick S ; Dobó, József ; Kjaer, Troels R ; Sirotkina, Sofia ; Yatime, Laure ; Sottrup-Jensen, Lars ; Thiel, Steffen ; Gál, Péter ; Andersen, Gregers Rom. / Structural basis for activation of the complement system by component C4 cleavage. I: Proceedings of the National Academy of Sciences of the United States of America. 2012 ; Bind 109, Nr. 38. s. 15425-15430.

Bibtex

@article{ff8ec9d3328f4ae5b31a9df56e9d8582,
title = "Structural basis for activation of the complement system by component C4 cleavage",
abstract = "An essential aspect of innate immunity is recognition of molecular patterns on the surface of pathogens or altered self through the lectin and classical pathways, two of the three well-established activation pathways of the complement system. This recognition causes activation of the MASP-2 or the C1s serine proteases followed by cleavage of the protein C4. Here we present the crystal structures of the 203-kDa human C4 and the 245-kDa C4⋅MASP-2 substrate⋅enzyme complex. When C4 binds to MASP-2, substantial conformational changes in C4 are induced, and its scissile bond region becomes ordered and inserted into the protease catalytic site in a manner canonical to serine proteases. In MASP-2, an exosite located within the CCP domains recognizes the C4 C345C domain 60 {\AA} from the scissile bond. Mutations in C4 and MASP-2 residues at the C345C-CCP interface inhibit the intermolecular interaction and C4 cleavage. The possible assembly of the huge in vivo enzyme-substrate complex consisting of glycan-bound mannan-binding lectin, MASP-2, and C4 is discussed. Our own and prior functional data suggest that C1s in the classical pathway of complement activated by, e.g., antigen-antibody complexes, also recognizes the C4 C345C domain through a CCP exosite. Our results provide a unified structural framework for understanding the early and essential step of C4 cleavage in the elimination of pathogens and altered self through two major pathways of complement activation.",
keywords = "crystallography, pattern recognition, proteolysis, structural biology",
author = "Kidmose, {Rune T} and Laursen, {Nick S} and J{\'o}zsef Dob{\'o} and Kjaer, {Troels R} and Sofia Sirotkina and Laure Yatime and Lars Sottrup-Jensen and Steffen Thiel and P{\'e}ter G{\'a}l and Andersen, {Gregers Rom}",
year = "2012",
month = sep,
day = "18",
doi = "10.1073/pnas.1208031109",
language = "English",
volume = "109",
pages = "15425--15430",
journal = "Proceedings of the National Academy of Sciences of the United States of America",
issn = "0027-8424",
publisher = "The National Academy of Sciences of the United States of America",
number = "38",

}

RIS

TY - JOUR

T1 - Structural basis for activation of the complement system by component C4 cleavage

AU - Kidmose, Rune T

AU - Laursen, Nick S

AU - Dobó, József

AU - Kjaer, Troels R

AU - Sirotkina, Sofia

AU - Yatime, Laure

AU - Sottrup-Jensen, Lars

AU - Thiel, Steffen

AU - Gál, Péter

AU - Andersen, Gregers Rom

PY - 2012/9/18

Y1 - 2012/9/18

N2 - An essential aspect of innate immunity is recognition of molecular patterns on the surface of pathogens or altered self through the lectin and classical pathways, two of the three well-established activation pathways of the complement system. This recognition causes activation of the MASP-2 or the C1s serine proteases followed by cleavage of the protein C4. Here we present the crystal structures of the 203-kDa human C4 and the 245-kDa C4⋅MASP-2 substrate⋅enzyme complex. When C4 binds to MASP-2, substantial conformational changes in C4 are induced, and its scissile bond region becomes ordered and inserted into the protease catalytic site in a manner canonical to serine proteases. In MASP-2, an exosite located within the CCP domains recognizes the C4 C345C domain 60 Å from the scissile bond. Mutations in C4 and MASP-2 residues at the C345C-CCP interface inhibit the intermolecular interaction and C4 cleavage. The possible assembly of the huge in vivo enzyme-substrate complex consisting of glycan-bound mannan-binding lectin, MASP-2, and C4 is discussed. Our own and prior functional data suggest that C1s in the classical pathway of complement activated by, e.g., antigen-antibody complexes, also recognizes the C4 C345C domain through a CCP exosite. Our results provide a unified structural framework for understanding the early and essential step of C4 cleavage in the elimination of pathogens and altered self through two major pathways of complement activation.

AB - An essential aspect of innate immunity is recognition of molecular patterns on the surface of pathogens or altered self through the lectin and classical pathways, two of the three well-established activation pathways of the complement system. This recognition causes activation of the MASP-2 or the C1s serine proteases followed by cleavage of the protein C4. Here we present the crystal structures of the 203-kDa human C4 and the 245-kDa C4⋅MASP-2 substrate⋅enzyme complex. When C4 binds to MASP-2, substantial conformational changes in C4 are induced, and its scissile bond region becomes ordered and inserted into the protease catalytic site in a manner canonical to serine proteases. In MASP-2, an exosite located within the CCP domains recognizes the C4 C345C domain 60 Å from the scissile bond. Mutations in C4 and MASP-2 residues at the C345C-CCP interface inhibit the intermolecular interaction and C4 cleavage. The possible assembly of the huge in vivo enzyme-substrate complex consisting of glycan-bound mannan-binding lectin, MASP-2, and C4 is discussed. Our own and prior functional data suggest that C1s in the classical pathway of complement activated by, e.g., antigen-antibody complexes, also recognizes the C4 C345C domain through a CCP exosite. Our results provide a unified structural framework for understanding the early and essential step of C4 cleavage in the elimination of pathogens and altered self through two major pathways of complement activation.

KW - crystallography

KW - pattern recognition

KW - proteolysis

KW - structural biology

U2 - 10.1073/pnas.1208031109

DO - 10.1073/pnas.1208031109

M3 - Journal article

C2 - 22949645

VL - 109

SP - 15425

EP - 15430

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

SN - 0027-8424

IS - 38

ER -