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PDBsum entry 1z6c
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Blood clotting
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PDB id
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1z6c
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References listed in PDB file
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Key reference
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Title
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Solution structure of the ca2+-Binding egf3-4 pair from vitamin k-Dependent protein s: identification of an unusual fold in egf3.
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Authors
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T.Drakenberg,
H.Ghasriani,
E.Thulin,
A.M.Thämlitz,
A.Muranyi,
A.Annila,
J.Stenflo.
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Ref.
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Biochemistry, 2005,
44,
8782-8789.
[DOI no: ]
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PubMed id
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Abstract
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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.
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