Dominant effects of mutations in the collagenous domain of mannose-binding protein.
Individuals heterozygous for mutant alleles encoding serum mannose-binding protein (MBP, also known as mannose-binding lectin) show increased susceptibility to infections caused by a wide range of pathogenic microorganisms. To investigate the molecular defects associated with heterozygosity, wild-type rat serum MBP polypeptides (MBP-A: 56% identical in sequence to human MBP) and rat MBP polypeptides containing mutations associated with human immunodeficiency have been coexpressed using a well-characterized mammalian expression system. The resulting proteins are secreted almost exclusively as heterooligomers that are defective in activating the complement cascade. Functional defects are caused by structural changes to the N-terminal collagenous and cysteine-rich domains of MBP, disrupting interactions with associated serine proteases. The dominant effects of the mutations demonstrate how the presence of a single mutant allele gives rise to the molecular defects that lead to the disease phenotype in heterozygous individuals.
Wallis
Russell
R
Department of Biochemistry, Glycobiology Institute, University of Oxford, Oxford, United Kingdom. rwallis@glycob.ox.ac.uk
D000818:Animals; D001667:Binding, Competitive; D002352:Carrier Proteins / Q000737:chemistry / Q000235:genetics* / Q000502:physiology*; D003094:Collagen / Q000737:chemistry; D037222:Collectins; D003168:Complement Fixation Tests; D050606:Mannose-Binding Protein-Associated Serine Proteases; D009154:Mutation; D017434:Protein Structure, Tertiary; D051381:Rats; D012697:Serine Endopeptidases / Q000378:metabolism
D002352:Carrier Proteins; D037222:Collectins; D003094:Collagen; D050606:Mannose-Binding Protein-Associated Serine Proteases; D012697:Serine Endopeptidases