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A link between the complement and coagulation cascades: Identification of physiological substrates of MASP-1 using proteomics


The complement system is an ancient and highly conserved component of innate defence against invading pathogens. Its activation occurs via three possible routes: the classical, the lectin and the alternative pathways, resulting in the sequential processing of serine protease zymogens to active enzymes, and ultimately lysis of the pathogen.

The first step in the lectin pathway is the binding of Mannan Binding Lectin (MBL) to an activator surface (e.g. bacteria), which triggers the activation of MBL associated serine proteases (MASPs). However, the compositions of the activation complex and in particular the substrate specificities of MASPs are currently unclear.

There are 3 MASPs, MASP-1, MASP-2 and MASP-3, but only the function of one of them (MASP-2) ha s been defined. There is thus a pressing need to delineate the roles of MASP-1 and MASP-3 and to identify their substrates.

Use of synthetic substrates shows that MASP-1 possesses a thrombin-like specificity and recent work shows that activation of lectin pathway leads to the formation of a fibrin clot. This suggests that the MBL-MASP-1 complex brings about the localised sequestration of a pathogen in addition to its lysis. However, the nature of the components linking MASP-1 to the coagulation pathway remain to be identified.

Therefore, the primary goal of the proposed studies is to use a proteomics strategy to identify physiological substrates for the MASPs, with particular emphasis on MASP-1. Truncated proteins, resulting from digestion of target substrates by the protease in question, will be detected by comparing the profiles of treated- and untreated samples and identified by mass spectrometry.

A further approach using a combinatorial peptide library will define the substrate specificity of MASP-1 in detail and may also lead to the development of specific inhibitors. The proposed studies will provide fundamental new information on key pathways of innate immunity.

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