Structural basis of mannan-binding lectin recognition by its associated serine protease MASP-1: implications for complement activation

Structure. 2011 Nov 9;19(11):1635-43. doi: 10.1016/j.str.2011.08.014.

Abstract

Complement activation contributes directly to health and disease. It neutralizes pathogens and stimulates immune processes. Defects lead to immunodeficiency and autoimmune diseases, whereas inappropriate activation causes self-damage. In the lectin and classical pathways, complement is triggered upon recognition of a pathogen by an activating complex. Here we present the first structure of such a complex in the form of the collagen-like domain of mannan-binding lectin (MBL) and the binding domain of its associated protease (MASP-1/-3). The collagen binds within a groove using a pivotal lysine side chain that interacts with Ca(2+)-coordinating residues, revealing the essential role of Ca(2+). This mode of binding is prototypic for all activating complexes of the lectin and classical pathways, and suggests a general mechanism for the global changes that drive activation. The structural insights reveal a new focus for inhibitors and we have validated this concept by targeting the binding pocket of the MASP.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Motifs
  • Amino Acid Sequence
  • Binding Sites
  • Calcium / chemistry
  • Complement Activation*
  • Coordination Complexes / chemistry
  • Crystallography, X-Ray
  • Humans
  • Hydrogen Bonding
  • Mannose-Binding Lectin / chemistry*
  • Mannose-Binding Protein-Associated Serine Proteases
  • Models, Molecular
  • Molecular Sequence Data
  • Protein Binding
  • Protein Interaction Domains and Motifs
  • Protein Structure, Quaternary
  • Thermodynamics

Substances

  • Coordination Complexes
  • Mannose-Binding Lectin
  • Mannose-Binding Protein-Associated Serine Proteases
  • Masp1 protein, rat
  • Calcium

Associated data

  • PDB/3POB
  • PDB/3POD
  • PDB/3POE
  • PDB/3POF
  • PDB/3POG
  • PDB/3POJ
  • PDB/3POL
  • PDB/3PON