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The X-ray Crystal Structure of Mannose-Binding Lectin-Associated Serine Proteinase-3

Published: Thursday, June 27, 2013
Last Updated: Thursday, June 27, 2013
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These data reveal substantial perturbation of the active site, consistent with a correlation between the lack of MASP-3 function and the 3MC syndrome.

SUMMARY
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.


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