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

Søren E. Degn, Troels R. Kjaer, Rune T. Kidmose, Lisbeth Jensen, Annette G. Hansen, Mustafa Tekin, Jens C. Jensenius, Gregers R. Andersen, Steffen Thiel

Research output: Contribution to journalArticle

37 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)13445-13450
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume111
Issue number37
DOIs
StatePublished - Sep 16 2014

Keywords

  • Collectin
  • Homeostasis
  • Inflammation
  • Innate immunity

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    Degn, S. E., Kjaer, T. R., Kidmose, R. T., Jensen, L., Hansen, A. G., Tekin, M., Jensenius, J. C., Andersen, G. R., & 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, 111(37), 13445-13450. https://doi.org/10.1073/pnas.1406849111