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Crystal structure of the von Willebrand factor A domain of human capillary morphogenesis protein 2: an anthrax toxin

D Borden Lacy1, Darran J Wigelsworth, Heather M Scobie

  • 1Department of Microbiology and Molecular Genetics, Harvard Medical School, 200 Longwood Avenue, Boston, MA 02115, USA.

Proceedings of the National Academy of Sciences of the United States of America
|April 14, 2004
PubMed

Insights

Structural insights into anthrax toxin receptor CMG2 reveal its interaction with protective antigen (PA). This research provides a template for understanding toxin entry and developing new anthrax therapies.

Area of Science:

  • Structural biology
  • Biochemistry
  • Molecular biology

Background:

  • Anthrax toxin, secreted by Bacillus anthracis, comprises three proteins that form toxic complexes on host cells.
  • Protective antigen (PA) mediates toxin entry by binding to cellular receptors, including CMG2.
  • CMG2 is a type 1 membrane protein featuring a von Willebrand factor A (VWA) domain with a metal ion-dependent adhesion site (MIDAS).

Purpose of the Study:

  • To determine the crystal structure of the CMG2 VWA domain.
  • To provide a structural basis for understanding the high-affinity interaction between CMG2 and PA.
  • To aid in the development of novel anthrax treatments.

Main Methods:

  • X-ray crystallography was used to determine the structure of the CMG2 VWA domain.
  • Structures were solved to 1.5 and 1.8 Å resolution, with and without a disulfide bond.
  • Analysis of ligand binding at the MIDAS motif and comparison with other VWA domains.

Main Results:

  • The crystal structures of the CMG2 VWA domain were determined.
  • Both structures revealed a carboxylate ligand-mimetic bound at the MIDAS.
  • The CMG2 VWA domain adopts an open conformation compared to alpha-integrin VWA domains.

Conclusions:

  • The CMG2 VWA domain structure offers a template for studying the CMG2-PA interaction.
  • Understanding this interaction can facilitate research into anthrax toxin assembly and internalization.
  • Structural data may guide the development of new therapeutic strategies against anthrax and interpret disease-related mutations.

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