Structure of a von Willebrand Factor Cleaving Protease, an ADAMTS Protease Involved in Thrombotic Thrombocytopenic Purpura (TTP)

Reviewer: Mary Kara Bucci, MD
The Abramson Cancer Center of the University of Pennsylvania
Last Modified: December 9, 2001

Presenter: Dominic Chung
Presenter's Affiliation:
Type of Session: Plenary

Von Willebrand Factor Cleaving Protease (VWFCP) is a plasma metalloprotease that cleaves von Willebrand Factor multimer to smaller sizes. Deficiency of this protease, either congenital or associated with an auto-antibody, is associated with TTP. The purpose of this study was to identify and characterize this protease.

Materials and Methods

  • VWFCP was purified, identified as a 200 kDa glycoprotein, and sequenced
  • The genes for both human and mouse VWFCP were mapped
  • cDNA libraries were screened for overlapping human cDNA clones
  • Northern blotting of human mRNA was performed on multiple tissues in order to identify a likely site of VWFCP synthesis.


  • The determination of the N-terminal protein sequence identified VWFCP as a member of the ADAMTS metalloprotease family
  • The human and mouses genes for VWFCP, located on chromosomes 9 and 2, respectively, are highly conserved, with a 37kb domain (29 exons) in common. The protein sequences from the human and mouse genes are 70% identical.
  • The calculated mass of human VWFCP was 147 kDa (1353 residues), with potential glycosylation sites that would increase the mass to 200 kDa (the measured size).
  • A relatively long (4.7 KB) mRNA was identified in liver, implying liver may be a site of VWFCP synthesis.
  • The metalloprotease domain contains potential binding sites for calcium and zinc ions, consistent with the known sensitivity of VWFCP to chelation by calcium and zinc ions.
  • An RGD sequence, a potential site for binding to integrins, such as on platelets, has been identified within the ADAMTS spacer.
  • As many as seven different variants of VWFCP with unknown functional significance may be created by alternative splicing of the VWFCP gene.

    Author's Conclusions

  • VWFCP is identified as a member of the ADAMTS metalloprotease family and the gene mapped to chromosome 9q 34 in humans (chromosome 2 in mice).
  • Sites on the gene that code for known functions of VWFCP have been identified.
  • Liver may be a site of VWFCP synthesis.
  • VWFCP may have different forms, created by alternate splicing, that have different functions in different tissues.

    Clinical/Scientific Implications
    Identification and characterization of VWFCP has allowed it to be mapped to specific gene located on the long arm of chromosome 9. Recognizable structural motifs within the genome provide important information on the mechanisms of action of VWFCP. The potential products of alternative splicing may have different forms in different tissues; this is currently under further study.

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