RGD Reference Report - Decoupling of carbohydrate binding and MASP-2 autoactivation in variant mannose-binding lectins associated with immunodeficiency. - Rat Genome Database

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Decoupling of carbohydrate binding and MASP-2 autoactivation in variant mannose-binding lectins associated with immunodeficiency.

Authors: Wallis, R  Lynch, NJ  Roscher, S  Reid, KB  Schwaeble, WJ 
Citation: Wallis R, etal., J Immunol. 2005 Nov 15;175(10):6846-51.
RGD ID: 1582134
Pubmed: PMID:16272342   (View Abstract at PubMed)

Mannan-binding lectin (MBL) initiates complement activation by binding to arrays of carbohydrates on the surfaces of pathogenic microorganisms and activating MBL-associated serine proteases (MASPs). Separate point mutations to the collagenous domain of human MBL are associated with immunodeficiency, caused by reduced complement activation by the variant MBLs as well as by lower serum MBL concentrations. In the work reported here, we have used the well characterized rat lectin pathway to analyze the molecular and functional defects associated with two of the variant proteins. Mutations Gly25 --> Asp and Gly28 --> Glu create comparable structural changes in rat MBL but the G28E variant activates complement >10-fold less efficiently than the G25D variant, which in turn has approximately 7-fold lower activity than wild-type MBL. Analysis of mutant MBL . MASP-2 complexes assembled from recombinant components shows that reduced complement activation by both mutant MBLs is caused by failure to activate MASP-2 efficiently on binding to a mannan-coated surface. Disruption of MBL-MASP-2 interactions as well as to changes in oligomeric structure and reduced binding to carbohydrate ligands compared with wild-type MBL probably account for the intermediate phenotype of the G25D variant. However, carbohydrate binding and MASP-2 activation are ostensibly completely decoupled in complexes assembled from the G28E mutant, such that the rate of MASP-2 activation is no greater than the basal rate of zymogen MASP-2 autoactivation. Analogous molecular defects in human MBL probably combine to create the mutant phenotypes of immunodeficient individuals.



Gene Ontology Annotations    Click to see Annotation Detail View

Biological Process

  
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
Mbl1Ratcomplement activation, lectin pathway  IDA  RGD 

Molecular Function

  
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
Mbl1RatD-mannose binding  IDA  RGD 
Mbl1Ratpolysaccharide binding  IDA  RGD 
Mbl1Ratprotease binding  IDA MASP-2RGD 

Objects Annotated

Genes (Rattus norvegicus)
Mbl1  (mannose binding lectin 1)


Additional Information