1. C5b6789 Terminal complex C3 C3b C5 C5b C9 C8 C7 C6 C5a C3a C4a + C2b C3 C3b C3bBb Factor B Factor D C1q + C1r + C1s C3bBb3b activated C1s MBL/Ficolins + MASP-1 MASP-2 MASP-3 Ba C2 + C4 C4b2a C4b2a3b Classical pathway Lectin pathway Alternative pathway C3(H 2 O)Bb C3bB Figure 1.1. Schematic overview of the complement system. The three activation pathways all merge in the formation of a C3 convertase complex. After formation of the C3 convertase the C5 convertase complex can be generated enabling the formation of the terminal complex (or membrane attack complex) which can be formed on exposed plasma membranes. The cleavage products in red all have anaphylotoxin effects of which C5a is the most potent.

2. Figure 1.2. The mechanism by which C4b or C3b is bound covalently to a surface. Upon activation/cleavage of C4 structural rearrangements occur whereby the thiolester bond in C4b becomes exposed and reacts with active groups on nearby surfaces (R). This results in formation of an ester or amide bond between C4b or C3b and the surface. The figure was adapted from Law and Dodds (1997).

3. Figure 1.3. The polypeptide structure of C3 and its activation and degradation products. The position of the internal thiolester bond is indicated by a triangle, which upon conversion of C3 into C3b is broken and indicated by two parallel lines. The figure is modified from Law and Dodds, (1997).

4. Figure 1.4. A schematic representation of the C1 complex. Panel A shows C1 from the side while panel B shows it from below. The catalytic domain of C1rA is purple and of C1rB brown, while the CUB2 modules of the two C1r molecules are colored gray. For clarity the CUB and the catalytic domains of C1s have been omitted. This figure is adapted from Gregory et al., (2003). A B

5. Figure 1.5. The assembly of the hexameric MBL oligomer. Three MBL polypeptide chains associate generating the trimeric subunit. The MBL subunits can further associate to complexes composed of 2-6 trimeric subunits (here only the hexamer is shown). This figure is adapted from Presanis et al., (2003). x3 x6 Polypeptide chain Trimeric subunit Hexameric oligomer

6. Figure 1.6. Exon organization of the human ficolin genes. The boxes depict the exon structure of the ficolins and the corresponding protein domains are indicated by the ficolin subunit below for L-ficolin (L-FCN), M-ficolin (M-FCN) and H-ficolin (H-FCN). Modified from Endo et al., (2007).

7. Figure 1.7. The subunit structure of MBL and the ficolins, drawn approximately to scale regarding the length of the collagen-like domain. The break in the collagen-like domain indicates the position of the disruption in the Gly-Xaa-Yaa triplets. The figure is modified from Holmskov et al., (2003).

8. H-ficolinM-ficolin L-ficolin5383 M-ficolin52 Figure 1.8. Similarity between L-ficolin, M-ficolin and H-ficolin. Panel A shows an alignment of L-ficolin (SWISS-Prot entry: Q15485), M-ficolin (SWISS-Prot entry: O00602) and H-ficolin (Swiss-Prot entry: O75636) primary sequence. The alignment was performed with the ClustalW program (http://www.ebi.ac.uk/Tools/clustalw/index.html). The asterisks (*) represent exact matches, (:) represent conservative substitutions and (.) represent semi-conservative substitutions. The sequence in red is considered a part of the fbg domain. Panel B shows the pair-wise identity of the three ficolins in the fbg domain.http://www.ebi.ac.uk/Tools/clustalw/index.html A B

9. Figure 1.9. Schematic diagram of the L-ficolin trimeric subunit and the L-ficolin tetramer. This figure is modified from Ohashi and Erickson, (1998)

10. Figure 1.10. Structure of the L-ficolin fbg domain. Panel A shows the crystal structure of the L-ficolin trimeric subunit (seen from below). The amino acid side chains involved in the recognition of the ligands in the four recognition sites are coloured as follows: S1 (green), S2 (red), S3 (black) and S4 (orange). A Ca 2+ ion (yellow) is also found in the domain, but it is not directly involved in the ligand recognition. Panel B shows the proposed collaboration between sites S2-4 in mediating binding to oligosaccharides. This figure is adapted from Garlatti et al., (2007a). A B

11. Figure 1.11. The structure of the fbg domain of M-ficolin. The structure of the M- ficolin trimer with a GlcNAc molecule (green) at the predicted binding site seen from below (top) and the side (bottom). The 50 Å a rough indication of the dimensions of the molecule. This figure is adapted from Tanio et al., (2006).

12. Figure 1.12. The structure of the H-ficolin fbg domain. The amino acid side chains involved in the ligand recognition are shown in green. The yellow sphere is a Ca 2+ ion. This figure is adapted from Garlatti et al., (2007a).

13. Figure 1.13. Genomic organization and protein structure of the MASP1/3 and MASP2/MAp19 genes. Shown is the intron-exon structure of the two genes and their protein products. The arrow indicates the Arg-Ile bond that is cleaved upon MASP activation. The asterisks denotes potential N-linked glycosylation sites. The figure is modified from Schwaeble et al., (2002) 1 23 45 7 86 11 109 14 12 13 11 16 17 15 1 23 45 7 86109 12

14. Figure 1.14. The homodimeric structure of MAp19. Top view (top) and side view (bottom) of the homodimeric MAp19 complex. The amino acid side chains involved in the interactions between the two MAp19 molecules are indicated. The Ca 2+ ions are represented as golden spheres. This figure is adapted from Gregory et al., (2004).