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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.

Drakenberg T, Ghasriani H, Thulin E, Thämlitz AM, Muranyi A, Annila A, Stenflo J
Biochemistry 44 8782-9 (2005)
Cited: 11 times
EuropePMC logo PMID: 15952784

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 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.

Reviews - 1z6c mentioned but not cited (1)

  1. Protein C anticoagulant and cytoprotective pathways. Griffin JH, Zlokovic BV, Mosnier LO. Int J Hematol 95 333-345 (2012)

Articles - 1z6c mentioned but not cited (1)

  1. The dipeptidyl peptidase IV inhibitors vildagliptin and K-579 inhibit a phospholipase C: a case of promiscuous scaffolds in proteins. Chakraborty S, Rendón-Ramírez A, Ásgeirsson B, Dutta M, Ghosh AS, Oda M, Venkatramani R, Rao BJ, Dandekar AM, Goñi FM. F1000Res 2 286 (2013)


Reviews citing this publication (3)

  1. Structures of thrombospondins. Carlson CB, Lawler J, Mosher DF. Cell Mol Life Sci 65 672-686 (2008)
  2. Protein S: A multifunctional anticoagulant vitamin K-dependent protein at the crossroads of coagulation, inflammation, angiogenesis, and cancer. Suleiman L, Négrier C, Boukerche H. Crit Rev Oncol Hematol 88 637-654 (2013)
  3. Activated protein C anticoagulant system dysfunction and thrombophilia in Asia. Hamasaki N, Kuma H, Tsuda H. Ann Lab Med 33 8-13 (2013)

Articles citing this publication (6)

  1. Interactions among the epidermal growth factor-like modules of thrombospondin-1. Liu Y, Annis DS, Mosher DF. J Biol Chem 284 22206-22212 (2009)
  2. Binding of calcium to anticoagulant protein S: role of the fourth EGF module. Persson KE, Stenflo J, Linse S, Stenberg Y, Preston RJ, Lane DA, Rezende SM. Biochemistry 45 10682-10689 (2006)
  3. Molecular bases of type II protein S deficiency: the I203-D204 deletion in the EGF4 domain alters GLA domain function. Baroni M, Mazzola G, Kaabache T, Borgel D, Gandrille S, Vigano' D'Angelo S, Marchetti G, di Iasio MG, Pinotti M, D'Angelo A, Bernardi F. J Thromb Haemost 4 186-191 (2006)
  4. NMR spectroscopic and bioinformatic analyses of the LTBP1 C-terminus reveal a highly dynamic domain organisation. Robertson IB, Handford PA, Redfield C. PLoS One 9 e87125 (2014)
  5. One novel and one recurrent mutation in the PROS1 gene cause type I protein S deficiency in patients with pulmonary embolism associated with deep vein thrombosis. Mizukami K, Nakabayashi T, Naitoh S, Takeda M, Tarumi T, Mizoguchi I, Ieko M, Koike T. Am J Hematol 81 787-797 (2006)
  6. From gamma-carboxy-glutamate to protein C. Stenflo J. J Thromb Haemost 4 2521-2526 (2006)


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