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

Degn, Søren.E.; Kjaer, T.R.; Kidmose, R.T.; Jensen, L.; Hansen, A.G.; Tekin, M.; Jensenius, J.C.; Andersen, G.R.; Thiel, S.

Proceedings of the National Academy of Sciences of the United States of America 111(37): 13445-13450

2014


ISSN/ISBN: 0027-8424
PMID: 25197071
DOI: 10.1073/pnas.1406849111
Accession: 052255054

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.

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