1z6c

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Solution structure of an EGF pair (EGF34) from vitamin K-dependent protein S

Contents 1 Overview 2 Disease 3 About this Structure 4 Reference

Overview

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 psi angle of Glu186 from 160 degrees +/- 40 degrees , as, seen in ten other EGF domains, to approximately 0 degrees +/- 15 degrees ., 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.

Disease

Known diseases associated with this structure: Fletcher factor deficiency OMIM:[229000], Prekallikrein deficiency OMIM:[229000]

About this Structure

1Z6C is a Single protein structure of sequence from Homo sapiens with CA as ligand. Full crystallographic information is available from OCA.

Reference

Solution structure of the Ca2+-Binding EGF3-4 pair from vitamin K-dependent protein S: identification of an unusual fold in EGF3., Drakenberg T, Ghasriani H, Thulin E, Thamlitz AM, Muranyi A, Annila A, Stenflo J, Biochemistry. 2005 Jun 21;44(24):8782-9. PMID:15952784

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