Structural insights into the initiating complex of the lectin pathway of complement activation

Troels R Kjaer; Le T M Le; Jan Skov Pedersen; Bjoern Sander; Monika M Golas; Jens Christian Jensenius; Gregers R Andersen; Steffen Thiel

doi:10.1016/j.str.2014.10.024

Structural insights into the initiating complex of the lectin pathway of complement activation

Structure. 2015 Feb 3;23(2):342-51. doi: 10.1016/j.str.2014.10.024. Epub 2015 Jan 8.

Authors

Troels R Kjaer¹, Le T M Le², Jan Skov Pedersen³, Bjoern Sander⁴, Monika M Golas⁵, Jens Christian Jensenius¹, Gregers R Andersen⁶, Steffen Thiel⁷

Affiliations

¹ Department of Biomedicine, Aarhus University, Bartholins Allé 6 and Wilhelm Meyers Allé 3, 8000 Aarhus, Denmark.
² Department of Clinical Medicine, Aarhus University, Wilhelm Meyers Allé 3, 8000 Aarhus, Denmark.
³ Interdisciplinary Nanoscience Center (iNANO), Aarhus University, Gustav Wieds Vej 14, 8000 Aarhus, Denmark; Department of Chemistry, Aarhus University, Langelandsgade 140, 8000 Aarhus, Denmark.
⁴ Department of Clinical Medicine, Aarhus University, Wilhelm Meyers Allé 3, 8000 Aarhus, Denmark; Center for Stochastic Geometry and Advanced Bioimaging (CSGB), Aarhus University, Wilhelm Meyers Allé 3, 8000 Aarhus, Denmark.
⁵ Department of Biomedicine, Aarhus University, Bartholins Allé 6 and Wilhelm Meyers Allé 3, 8000 Aarhus, Denmark; Center for Stochastic Geometry and Advanced Bioimaging (CSGB), Aarhus University, Wilhelm Meyers Allé 3, 8000 Aarhus, Denmark.
⁶ Department of Molecular Biology and Genetics, Aarhus University, Gustav Wieds Vej 10, 8000 Aarhus, Denmark.
⁷ Department of Biomedicine, Aarhus University, Bartholins Allé 6 and Wilhelm Meyers Allé 3, 8000 Aarhus, Denmark. Electronic address: st@biomed.au.dk.

PMID: 25579818
DOI: 10.1016/j.str.2014.10.024

Abstract

The proteolytic cascade of the complement system is initiated when pattern-recognition molecules (PRMs) bind to ligands, resulting in the activation of associated proteases. In the lectin pathway of complement, the complex of mannan-binding lectin (MBL) and MBL-associated serine protease-1 (MASP-1) initiates the pathway by activating a second protease, MASP-2. Here we present a structural study of a PRM/MASP complex and derive the overall architecture of the 450 kDa MBL/MASP-1 complex using small-angle X-ray scattering and electron microscopy. The serine protease (SP) domains from the zymogen MASP-1 dimer protrude from the cone-like MBL tetramer and are separated by at least 20 nm. This suggests that intracomplex activation within a single MASP-1 dimer is unlikely and instead supports intercomplex activation, whereby the MASP SP domains are accessible to nearby PRM-bound MASPs. This activation mechanism differs fundamentally from the intracomplex initiation models previously proposed for both the lectin and the classical pathway.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Chromatography, Gel
Complement Activation / genetics
Complement Activation / physiology*
Complement Pathway, Mannose-Binding Lectin / genetics*
Complement Pathway, Mannose-Binding Lectin / physiology
Dimerization
Electrophoresis, Polyacrylamide Gel
Humans
Mannose-Binding Protein-Associated Serine Proteases / chemistry*
Mannose-Binding Protein-Associated Serine Proteases / metabolism
Microscopy, Electron
Models, Molecular*
Protein Conformation
Receptors, Pattern Recognition / chemistry*
Receptors, Pattern Recognition / metabolism
Scattering, Small Angle

Substances

Receptors, Pattern Recognition
MASP1 protein, human
Mannose-Binding Protein-Associated Serine Proteases