No abstract

No abstract

Mannose-binding lectin (MBL) is a collagen-like serum protein that mediates activation of the complement system and is of importance for host defence. Common variant alleles situated both in the promoter and structural region of the human MBL gene (MBL2) influence the stability and the serum concentration of the protein. Epidemiological studies have suggested that genetically determined variation in MBL serum concentration influences the susceptibility to and the course of different types of infections, autoimmune, metabolic and cardiovascular diseases, but this is still a subject of debate. The fact that these genetic variations are very frequent indicates a dual role for MBL in host defence. In this survey, we summarize the current molecular understanding of human MBL genetics.

Deficiency of human mannose-binding lectin (MBL)caused by mutations in the coding part of the MBL2 gene is associated with increased risk and severity of infections and autoimmunity. To study the biological consequences of MBL mutations, we expressed wild type MBL and mutated MBL in Chinese hamster ovary cells. The normal MBL cDNA (WT MBL-A) was cloned, and the three known natural and two artificial variants were expressed in Chinese hamster ovary cells. When analyzed, WT MBL-A formed covalently linked higher oligomers with a molecular mass of about 300 -450 kDa, corresponding to 12-18 single chains or 4 -6 structural units. By contrast, all MBL variants formed a dominant band of about 50 kDa, with increasingly weaker bands at 75, 100, and 125 kDa corresponding to two, three, four, and five chains, respectively. In contrast to WT MBL-A, variant MBL formed noncovalent oligomers containing up to six chains (two structural units). MBL variants bound ligands with a markedly reduced capacity compared with WT MBL-A. Mutations in the collagenous region of human MBL compromise assembly of higher order oligomers, resulting in reduced ligand binding capacity and thus reduced capability to activate complement. Mannose-binding lectin (MBL)1 has been shown to be an important component of innate immunity and is a central recognition molecule of the lectin pathway of complement (for a recent review, see Ref. 1). MBL binds to an array of carbohydrate structures on surfaces of bacteria (2-4), yeast, viruses (5, 6), and parasitic protozoa (7,8). MBL functions as an opsonin (9), and the biological effect is mediated by direct killing via complement (10) through the lytic membrane attack complex or by promoting phagocytosis either by the MBL lectin pathway of complement or by direct binding to one or more cell surface receptors (11). The lectin pathway comprises at least three MBL-associated serine proteases (MASPs), namely MASP-1 (12), MASP-2 (13), and . Furthermore, the functional MBL-MASP complex contains a small MBL-associated protein (sMAP), also named MAp19, with no serine protease activity (15, 16). MASP-2 is a homologue of C1s of the classical complement pathway because it activates C4 and C2 (13). When MBL associated with MASP-2 binds to sugar groups on the surface of microbes, the MBL-MASP2 proenzyme is activated and cleaves sequentially C4 and C2, thereby creating the C4b2a complex, a potent C3 convertase. The MBL-MASP-1 complex is suggested to activate C3 directly (12). Whether both MASP-1 and MASP-2 are bound on the same MBL molecule is still unclear. Moreover, the biological role of sMAP, as well as the substrate for the recently discovered MASP-3, remains unclear at this moment (for a recent review on MASPs, see Ref. 17).MBL is a complex of six sets of homotrimers of a single polypeptide chain containing 228 amino acids (18 -21). This polypeptide consists of four domains ( Fig. 1): 1) a 20-amino acid N-terminal cysteine-rich domain involved in formation of intraand intersubunit disulfide bonds, 2) a collagen-like dom...