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Disease-associated Mutations in Human Mannose-binding Lectin Compromise Oligomerization and Activity of the Final Protein
Ist Teil von
The Journal of biological chemistry, 2004-05, Vol.279 (20), p.21302-21311
Ort / Verlag
United States: American Society for Biochemistry and Molecular Biology
Erscheinungsjahr
2004
Quelle
MEDLINE
Beschreibungen/Notizen
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.