Structural Basis of Mannan-Binding Lectin Recognition by Its Associated Serine Protease MASP-1: Implications for Complement Activation

Gingras, A. R. et al. Structure. 2011. 19: 1635–1643

Speaker: Sheng-huei Lin Chung (林張聖彙)   )                   Time : 14:10~ :15:00, Mar. 14, 2012

Commentator: Prof. Woei-Jer Chung (莊偉哲老師)  )       Place: Room 601

Abstract

The complement system is the first line of defense against microorganism in human diseases. The complement cascades are able to neutralize pathogens and stimulate key immunological processes upon binding to a pathogen surface¹. There are three pathways that activate the complement cascades: the classical, lectin and alternative pathways. In the lectin pathway, mannan-binding lectin (MBL) and serum ficolins bind to carbohydrates on pathogens to activate MBL-associated serine proteases (MASPs). To reveal how the lectin pathway is initiated, the authors solved the first crystal structure of the collagen-like domain of MBL in complex with the CUB2 binding domain of MASP, and propose a new model for the activation of lectin pathway. The structure shows that the interface of MBL and CUB2 is stabilized by hydrogen bonds and hydrophobic interactions, and the interface is relative small than other collagen-associated complexes. The residue Lys46 of MBL interacts with the Ca²⁺ -coordinating residues on CUB2 domain of MASP. This interaction supports a model of Ca²⁺-binding dependent activation for classical and lectinpathways. Relative binding orientation of MBL and MASP is inverted to previous model² and it supports a different complement activation process. The structural insights provide a starting point for inhibitors and this concept is certified by targeting the binding pocket of the MASP in this paper.

References

1. Jason R Dunkelberger, et al. Complement and its role in innate and adaptive immune responses. Cell Research. 2010. 20, 34-50.
2. Florence Teillet, et al. Crystal structure of the CUB ₁ -EGF-CUB ₂ domain of human MASP-1/3 and identification of its interaction sites with mannan-binding lectin and ficolins. The journal of biological chemistry. 2008. 283(37), 25715-25724.