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Exploring Protein-Glycan Interactions: Advances in Nuclear Magnetic Resonance
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Exploring Protein-Glycan Interactions: Advances in Nuclear Magnetic Resonance

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Two mechanisms for mannose-binding protein modulation of the activity of its associated serine proteases

Ce-Belle Chen1, Russell Wallis

  • 1Glycobiology Institute, Department of Biochemistry, University of Oxford, Oxford OX1 3QU, United Kingdom.

The Journal of Biological Chemistry
|April 3, 2004
PubMed

Insights

Mannose-binding protein (MBP) enhances the complement cascade by modulating mannose-binding lectin-associated serine proteases (MASPs). MBP stimulates MASP-2 autoactivation and regulates substrate binding for efficient microbial neutralization.

Area of Science:

  • Immunology
  • Biochemistry
  • Complement System

Background:

  • Serum mannose-binding protein (MBP) is crucial for innate immunity, neutralizing microbes by activating the complement cascade via mannose-binding lectin-associated serine proteases (MASPs).
  • MASP-2 plays a central role in activating the complement cascade by cleaving C2 and C4 components.

Purpose of the Study:

  • To elucidate the activation mechanisms and substrate recognition of MASP-2.
  • To investigate how MBP modulates MASP-2 activity and its role in complement activation.

Main Methods:

  • Production of zymogen and activated forms of MASP-2.
  • Creation of MBP.MASP-2 complexes.
  • Analysis of MBP's modulatory effects on MASP-2 autoactivation and substrate binding using glycan-coated surfaces.

Main Results:

  • MBP stimulates MASP-2 autoactivation on glycan-coated surfaces, increasing autocatalysis rates.
  • MBP initially occludes accessory C4-binding sites on MASP-2, exposing them upon activation to facilitate C4 binding and cleavage.
  • Activated MASP-2 binds C2, suggesting its interaction is near the catalytic site, while MASP-1 efficiently cleaves C2 but not C4.

Conclusions:

  • MBP plays a dual role in regulating MASP-2 activity, promoting autoactivation and controlling substrate access.
  • The findings reveal detailed mechanisms of complement activation initiated by MBP.MASP-2 complexes.
  • MASP-1 enhances complement activation initiated by MBP.MASP-2 but cannot initiate it independently.

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