Solution Structure of the Ca(2+)-Binding EGF3-4 Pair from Vitamin K-Dependent Protein S: Identification of an Unusual Fold in EGF3(,).
(2005) In Biochemistry 44(24). p.8782-8789- Abstract
- 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... (More)
- 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. (Less)
Please use this url to cite or link to this publication:
https://lup.lub.lu.se/record/140052
- author
- Drakenberg, Torbjörn LU ; Ghasriani, Houman LU ; Thulin, Eva LU ; Thämlitz, Ann-Marie LU ; Muranyi, Andreas ; Annila, Arto and Stenflo, Johan LU
- organization
- publishing date
- 2005
- type
- Contribution to journal
- publication status
- published
- subject
- in
- Biochemistry
- volume
- 44
- issue
- 24
- pages
- 8782 - 8789
- publisher
- The American Chemical Society (ACS)
- external identifiers
-
- wos:000229994900023
- pmid:15952784
- scopus:20544472145
- ISSN
- 0006-2960
- DOI
- 10.1021/bi050101f
- language
- English
- LU publication?
- yes
- id
- 1a5b3b1d-00c8-4182-945a-6ee5ffd35818 (old id 140052)
- date added to LUP
- 2016-04-01 11:49:55
- date last changed
- 2022-01-26 18:52:29
@article{1a5b3b1d-00c8-4182-945a-6ee5ffd35818, abstract = {{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.}}, author = {{Drakenberg, Torbjörn and Ghasriani, Houman and Thulin, Eva and Thämlitz, Ann-Marie and Muranyi, Andreas and Annila, Arto and Stenflo, Johan}}, issn = {{0006-2960}}, language = {{eng}}, number = {{24}}, pages = {{8782--8789}}, publisher = {{The American Chemical Society (ACS)}}, series = {{Biochemistry}}, title = {{Solution Structure of the Ca(2+)-Binding EGF3-4 Pair from Vitamin K-Dependent Protein S: Identification of an Unusual Fold in EGF3(,).}}, url = {{http://dx.doi.org/10.1021/bi050101f}}, doi = {{10.1021/bi050101f}}, volume = {{44}}, year = {{2005}}, }