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Complement activation by ligand-driven juxtaposition of discrete pattern recognition complexes

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Complement activation by ligand-driven juxtaposition of discrete pattern recognition complexes. / Degn, Søren E; Kjaer, Troels R; Kidmose, Rune Thomas et al.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 111, No. 37, 02.09.2014, p. 13445-13450.

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaperJournal articleResearchpeer-review

Harvard

Degn, SE, Kjaer, TR, Kidmose, RT, Jensen, L, Hansen, AG, Tekin, M, Jensenius, JC, Andersen, GR & Thiel, S 2014, 'Complement activation by ligand-driven juxtaposition of discrete pattern recognition complexes', Proceedings of the National Academy of Sciences of the United States of America, vol. 111, no. 37, pp. 13445-13450. https://doi.org/10.1073/pnas.1406849111

APA

CBE

MLA

Degn, Søren E et al. "Complement activation by ligand-driven juxtaposition of discrete pattern recognition complexes". Proceedings of the National Academy of Sciences of the United States of America. 2014, 111(37). 13445-13450. https://doi.org/10.1073/pnas.1406849111

Vancouver

Degn SE, Kjaer TR, Kidmose RT, Jensen L, Hansen AG, Tekin M et al. Complement activation by ligand-driven juxtaposition of discrete pattern recognition complexes. Proceedings of the National Academy of Sciences of the United States of America. 2014 Sep 2;111(37):13445-13450. doi: 10.1073/pnas.1406849111

Author

Degn, Søren E ; Kjaer, Troels R ; Kidmose, Rune Thomas et al. / Complement activation by ligand-driven juxtaposition of discrete pattern recognition complexes. In: Proceedings of the National Academy of Sciences of the United States of America. 2014 ; Vol. 111, No. 37. pp. 13445-13450.

Bibtex

@article{ff76c35bb03e415f8be5ffa4e392e3e4,
title = "Complement activation by ligand-driven juxtaposition of discrete pattern recognition complexes",
abstract = "Defining mechanisms governing translation of molecular binding events into immune activation is central to understanding immune function. In the lectin pathway of complement, the pattern recognition molecules (PRMs) mannan-binding lectin (MBL) and ficolins complexed with the MBL-associated serine proteases (MASP)-1 and MASP-2 cleave C4 and C2 to generate C3 convertase. MASP-1 was recently found to be the exclusive activator of MASP-2 under physiological conditions, yet the predominant oligomeric forms of MBL carry only a single MASP homodimer. This prompted us to investigate whether activation of MASP-2 by MASP-1 occurs through PRM-driven juxtaposition on ligand surfaces. We demonstrate that intercomplex activation occurs between discrete PRM/MASP complexes. PRM ligand binding does not directly escort the transition of MASP from zymogen to active enzyme in the PRM/MASP complex; rather, clustering of PRM/MASP complexes directly causes activation. Our results support a clustering-based mechanism of activation, fundamentally different from the conformational model suggested for the classical pathway of complement.",
author = "Degn, {S{\o}ren E} and Kjaer, {Troels R} and Kidmose, {Rune Thomas} and Lisbeth Jensen and Hansen, {Annette G} and Mustafa Tekin and Jensenius, {Jens C} and Andersen, {Gregers R} and Steffen Thiel",
year = "2014",
month = sep,
day = "2",
doi = "10.1073/pnas.1406849111",
language = "English",
volume = "111",
pages = "13445--13450",
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 = "37",

}

RIS

TY - JOUR

T1 - Complement activation by ligand-driven juxtaposition of discrete pattern recognition complexes

AU - Degn, Søren E

AU - Kjaer, Troels R

AU - Kidmose, Rune Thomas

AU - Jensen, Lisbeth

AU - Hansen, Annette G

AU - Tekin, Mustafa

AU - Jensenius, Jens C

AU - Andersen, Gregers R

AU - Thiel, Steffen

PY - 2014/9/2

Y1 - 2014/9/2

N2 - Defining mechanisms governing translation of molecular binding events into immune activation is central to understanding immune function. In the lectin pathway of complement, the pattern recognition molecules (PRMs) mannan-binding lectin (MBL) and ficolins complexed with the MBL-associated serine proteases (MASP)-1 and MASP-2 cleave C4 and C2 to generate C3 convertase. MASP-1 was recently found to be the exclusive activator of MASP-2 under physiological conditions, yet the predominant oligomeric forms of MBL carry only a single MASP homodimer. This prompted us to investigate whether activation of MASP-2 by MASP-1 occurs through PRM-driven juxtaposition on ligand surfaces. We demonstrate that intercomplex activation occurs between discrete PRM/MASP complexes. PRM ligand binding does not directly escort the transition of MASP from zymogen to active enzyme in the PRM/MASP complex; rather, clustering of PRM/MASP complexes directly causes activation. Our results support a clustering-based mechanism of activation, fundamentally different from the conformational model suggested for the classical pathway of complement.

AB - Defining mechanisms governing translation of molecular binding events into immune activation is central to understanding immune function. In the lectin pathway of complement, the pattern recognition molecules (PRMs) mannan-binding lectin (MBL) and ficolins complexed with the MBL-associated serine proteases (MASP)-1 and MASP-2 cleave C4 and C2 to generate C3 convertase. MASP-1 was recently found to be the exclusive activator of MASP-2 under physiological conditions, yet the predominant oligomeric forms of MBL carry only a single MASP homodimer. This prompted us to investigate whether activation of MASP-2 by MASP-1 occurs through PRM-driven juxtaposition on ligand surfaces. We demonstrate that intercomplex activation occurs between discrete PRM/MASP complexes. PRM ligand binding does not directly escort the transition of MASP from zymogen to active enzyme in the PRM/MASP complex; rather, clustering of PRM/MASP complexes directly causes activation. Our results support a clustering-based mechanism of activation, fundamentally different from the conformational model suggested for the classical pathway of complement.

U2 - 10.1073/pnas.1406849111

DO - 10.1073/pnas.1406849111

M3 - Journal article

C2 - 25197071

VL - 111

SP - 13445

EP - 13450

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 - 37

ER -