Structures of the MASP Proteases and Comparison with Complement C1r and C1s

Abstract

Several recognition proteins of the defence collagen family associate with proteases to initiate the complement cascade. The associated proteases, which are the subject of this review, mediate the proteolytic activation trigger. MBL--associated serine proteases (MASPs) mainly activate the lectin complement pathway (LP), while C1r and C1s activate the classical complement pathway (CP). This chapter will briefly introduce the current structural knowledge on these effector proteases and question what we know on MASPs structures, their common properties and how they differ from the C1r/s proteases. We will primarily focus on the structural comparison of the N--terminal domains, where the collectin binding sites are located and highlight novel aspects on their interaction with collagens. We also aim to highlight further molecular details associated to functional specificities, and to mention questions remaining open and needing further investigations. This chapter complements other reviews that describe the main general lines of complement activation mechanisms (1), the proposed structure--based scheme of the lectin pathway activation (2) and previous comparisons of LP and CP proteases (3,4).1. Common protease modular structure and mode of interaction with defence collagens MASP--1, MASP--2, MASP--3, C1r and C1s serine proteases share identical mosaic organization (Figure 1). The enzymatic activity of their C--terminal serine protease (SP) domain is controlled by the five preceding modules: two CUB (for complement C1r/C1s, Uegf, Bmp1) modules separated by an epidermal growth factor (EGF)--like module, and a pair of complement control protein (CCP) modules. LP and CP proteases are synthesized as single polypeptide chain proenzymes and become activated when a specific Arg-Ile bond is cleaved after the activation peptide in the SP domain, resulting in two chains, A and B, held together by a disulphide bridge (Figure 1). As will be detailed later, the activation cleavage is mainly triggered when the associated defence collagen binds to a target surface.Alternative splicing products also modulate LP activity. MASP--1 and MASP--3 are the products of a single MASP1 gene. They contain identical A chains (except for the 15 C--terminal