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Solution Structure of the Ca(2+)-Binding EGF3-4 Pair from Vitamin K-Dependent Protein S: Identification of an Unusual Fold in EGF3(,).

In English

Författare

  • Torbjörn Drakenberg
  • Houman Ghasriani
  • Eva Thulin
  • Ann-Marie Thämlitz
  • Andreas Muranyi
  • Arto Annila
  • Johan Stenflo

Summary, in English

Vitamin K-dependent protein S is a cofactor of activated protein C, a serine protease that regulates blood coagulation. Deficiency of protein S can cause venous thrombosis. Protein S has four EGF domains in tandem; domains 2-4 bind calcium with high affinity whereas domains 1-2 mediate interaction with activated protein C. We have now solved the solution structure of the EGF3-4 fragment of protein S. The linker between the two domains is similar to what has been observed in other calcium-binding EGF domains where it provides an extended conformation. Interestingly, a disagreement between NOE and RDC data revealed a conformational heterogeneity within EGF3 due to a hinge-like motion around Glu186 in the Cys-Glu-Cys sequence, the only point in the domain where flexibility is allowed. The dominant, bent conformation of EGF3 in the pair has no precedent among calcium-binding EGF domains. It is characterized by a change in the angle of Glu186 from 160 ± 40, as seen in ten other EGF domains, to 0 ± 15. NOESY data suggest that Tyr193, a residue not conserved in other calcium-binding EGF domains (except in the homologue Gas6), induces the unique fold of EGF3. However, SAXS data, obtained on EGF1-4 and EGF2-4, showed a dominant, extended conformation in these fragments. This may be due to a counterproductive domain-domain interaction between EGF2 and EGF4 if EGF3 is in a bent conformation. We speculate that the ability of EGF3 to adopt different conformations may be of functional significance in protein-protein interactions involving protein S.

Publiceringsår

2005

Språk

Engelska

Sidor

8782-8789

Publikation/Tidskrift/Serie

Biochemistry

Volym

44

Issue

24

Dokumenttyp

Artikel i tidskrift

Förlag

The American Chemical Society (ACS)

Ämne

  • Biochemistry and Molecular Biology

Status

Published

Forskningsgrupp

  • Clinical Chemistry, Malmö

ISBN/ISSN/Övrigt

  • ISSN: 0006-2960