The X-ray Crystal Structure of Mannose-Binding Lectin-Associated Serine Proteinase-3
News Jun 27, 2013
The mannose-binding lectin associatedprotease-3 (MASP-3) is a member of the lectin pathway of the complement system, a key component of human innate and active immunity. Mutations in MASP-3 have recently been found to be associated with Carnevale, Mingarelli, Malpuech and Michels (3MC) syndrome, a severe developmental disorder manifested by cleft palate, intellectual disability and skeletal abnormalities. However, the molecular basis for MASP-3 function remains to be understood. Here we characterise the substrate specificity of MASP-3 by screening against a combinatorial peptide substrate library. Through this approach, we successfully identified a peptide substrate that was 20-fold more efficiently cleaved than any other identified to date. Further, we demonstrated that mutant forms of the enzyme associated with 3MC syndrome were completely inactive against this substrate. To address the structural basis for this defect, we determined the 2.6 Å structure of the zymogen form of the G666E mutant of MASP-3. These data reveal that the mutation disrupts the active site and perturbs the position of the catalytic serine residue. Together, these insights into the function of MASP-3 reveal how a mutation in this enzyme causes it to be inactive and thus contribute to the 3MC syndrome.
This article was published online in The Journal of Biological Chemistry and is free to access.
Biomarker for Glioblastoma Predicts Clinical Course and Sensitivity to TreatmentNews
Scientists validate a biomarker indicative of patients with Glioblastoma prognosis and likely response to specific therapies.READ MORE
A New Tactic in the Fight Against Drug-Resistant InfectionsNews
$1 million research grant could lead to life-saving antibiotics.READ MORE
Comments | 0 ADD COMMENT
Annual Conference on Antimicrobials and Drug Resistance
Sep 24 - Sep 25, 2018
1st Alpine Winter Conference on Medicinal and Synthetic Chemistry
Jan 28 - Feb 01, 2018