Localization and Characterization of the Mannose-binding Lectin (Mbl)-associated-serine Protease-2 Binding Site in Rat Ficolin-a: Equivalent Binding Sites Within the Collagenous Domains of Mbls and Ficolins.
From: Department of Biochemistry, Medical Research Council Immunochemistry Unit, University of Oxford, Oxford, United Kingdom.
Journal of immunology (Baltimore, Md. : 1950)
- Publish Date: Jul 2007
- ISSN: 0022-1767
- Volume: 179
- Issue: 1
- Pages: 455-62
- Medium: Print
- Language: English
- Citation (JAMA): Girija Umakhanth Venkatraman, Dodds Alister W, Roscher Silke, et al. Localization and Characterization of the Mannose-binding Lectin (Mbl)-associated-serine Protease-2 Binding Site in Rat Ficolin-a: Equivalent Binding Sites Within the Collagenous Domains of Mbls and Ficolins.. J. Immunol. Jul 2007;179:455-62
Abstract
Ficolins and mannose-binding lectins (MBLs) are the first components of the lectin branch of the complement system. They comprise N-terminal collagen-like domains and C-terminal pathogen-recognition domains (fibrinogen-like domains in ficolins and C-type carbohydrate-recognition domains in MBLs), which target surface-exposed N-acetyl groups or mannose-like sugars on microbial cell walls. Binding leads to activation of MBL-associated serine protease-2 (MASP-2) to initiate complement activation and pathogen neutralization. Recent studies have shown that MASP-2 binds to a short segment of the collagen-like domain of MBL. However, the interaction between ficolins and MASP-2 is relatively poorly understood. In this study, we show that the MASP-2 binding site on rat ficolin-A is also located within the collagen-like domain and encompasses a conserved motif that is present in both MBLs and ficolins. Characterization of this motif using site-directed mutagenesis reveals that a lysine residue in the X position of the Gly-X-Y collagen repeat, Lys(56) in ficolin-A, which is present in all ficolins and MBLs known to activate complement, is essential for MASP-2 binding. Adjacent residues also make important contributions to binding as well as to MASP activation probably by stabilizing the local collagen helix. Equivalent binding sites and comparable activation kinetics of MASP-2 suggest that complement activation by ficolins and MBLs proceeds by analogous mechanisms.
Mesh Headings (Keywords): Amino Acid Motifs, Amino Acid Sequence, Animals, Binding Sites, CHO Cells, Collagen, Complement Activation, Conserved Sequence, Cricetinae, Cricetulus, Kinetics, Lectins, Lysine, Mannose-Binding Lectins, Mannose-Binding Protein-Associated Serine Proteases, Molecular Sequence Data, Protein Binding, Protein Structure, Tertiary, Rats, Recombinant Proteins, Sequence Alignment, Substrate Specificity
Check for Full Text / PubMed Unique Identifier (PMID): 17579066
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