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PMID: 15079089 Published · ppublish English Journal Article Research Support, U.S. Gov't, P.H.S.

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

Proceedings of the National Academy of Sciences of the United States of America ·Vol. 101 ·No. 17 ·2004-04-27 ·Pages 6367-72

Lacy DB, Wigelsworth DJ, Scobie HM, Young JA, Collier RJ

Abstract

Anthrax toxin is released from Bacillus anthracis as three monomeric proteins, which assemble into toxic complexes at the surface of receptor-bearing host cells. One of the proteins, protective antigen (PA), binds to receptors and orchestrates the delivery of the other two (the lethal and edema factors) into the cytosol. PA has been shown to bind to two cellular receptors: anthrax toxin receptor/tumor endothelial marker 8 and capillary morphogenesis protein 2 (CMG2). Both are type 1 membrane proteins that include an approximately 200-aa extracellular von Willebrand factor A (VWA) domain with a metal ion-dependent adhesion site (MIDAS) motif. The anthrax toxin receptor/tumor endothelial marker 8 and CMG2 VWA domains share approximately 60% amino acid identity and bind PA directly in a metal-dependent manner. Here, we report the crystal structure of the CMG2 VWA domain, with and without its intramolecular disulfide bond, to 1.5 and 1.8 A, respectively. Both structures contain a carboxylate ligand-mimetic bound at the MIDAS and appear as open conformations when compared with the VWA domains from alpha-integrins. The CMG2 structures provide a template to begin probing the high-affinity CMG2-PA interaction (200 pM) and may facilitate understanding of toxin assembly/internalization and the development of new anthrax treatments. The structural data also allow molecular interpretation of known CMG2 VWA domain mutations linked to the genetic disorders, juvenile hyaline fibromatosis, and infantile systemic hyalinosis.

MeSH Terms
Amino Acid Sequence Crystallography, X-Ray Humans Membrane Proteins/chemistry Models, Molecular Molecular Sequence Data Protein Conformation Receptors, Peptide/chemistry Sequence Homology, Amino Acid von Willebrand Factor/chemistry
Chemicals
ANTXR2 protein, human Membrane Proteins Receptors, Peptide anthrax toxin receptors von Willebrand Factor
Authors & Affiliations
5 authors, click to expand affiliations / ORCID
Lacy D Borden
Department of Microbiology and Molecular Genetics, Harvard Medical School, 200 Longwood Avenue, Boston, MA 02115, USA.
Wigelsworth Darran J
Scobie Heather M
Young John A T
Collier R John
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Article Info
Journal
Proceedings of the National Academy of Sciences of the United States of America
Abbr.
Proc Natl Acad Sci U S A
ISSN
0027-8424
DOI
10.1073/pnas.0401506101
Published
2004-04-27
Epub
2004-00-12
Pages
6367-72
Language
English
Region
United States
NLM ID
7505876
PMCID
PMC404051
Subset
IM
Grants
NIAID NIH HHS · AI022021 · United States
NIAID NIH HHS · R01 AI048489 · United States
NIAID NIH HHS · AI056013 · United States
NIAID NIH HHS · AI048489 · United States
NIAID NIH HHS · R01 AI022021 · United States
NIAID NIH HHS · P01 AI056013 · United States
NIAID NIH HHS · R37 AI022021 · United States
Databases
PDB
1SHT, 1SHU
External Links
PubMed source DOI: 10.1073/pnas.0401506101 PMC Full Text View journal details
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