Structural Requirements of Anticoagulant Protein S for Its Binding to the Complement Regulator C4b-binding Protein

Giri, Tusar; Linse, Sara; Frutos, Pablo Garcı́a de; Yamazaki, Tomio; Villoutreix, Bruno O.; Dahlbäck, Björn

doi:10.1074/jbc.m103036200

Cited by 27 publications

(34 citation statements)

References 53 publications

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“…These results support a role of the protein S SHBG-like domain for the TFPI cofactor function as well as the direct interaction between protein S and TFPI. Interestingly, whereas both LG subunits have been shown to be important for the interaction with C4BP, [37][38][39] our results suggests that the LG1 subunit of the SHBG-like domain may be of greater importance than the LG2 subunit for binding TFPI.…”

Section: Tfpi Cofactor Function Of Protein S 3985mentioning

confidence: 65%

“…Both LG subunits are believed to be involved in the interaction with this protein, but despite numerous attempts, the interaction site has not been precisely identified. [37][38][39] Hackeng et al have previously shown that the addition of a molar excess of C4BP to free protein S in normal plasma resulted in a 40% decrease of the TFPI enhancement by protein S in thrombin-generation assays. 15 In addition, immunodepletion experiments showed that protein S Figure 5.…”

Section: Discussionmentioning

confidence: 99%

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TFPI cofactor function of protein S: essential role of the protein S SHBG-like domain

Reglińska-Matveyev

Andersson

Rezende

et al. 2014

Blood

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Key Points• The protein S SHBG-like domain and, more specifically, its LG1 subunit are important for binding and enhancement of TFPI.• TFPI binding to the protein S SHBG-like domain likely positions TFPI Kunitz domain 2 for optimal interaction with the active site of FXa.Protein S is a cofactor for tissue factor pathway inhibitor (TFPI), accelerating the inhibition of activated factor X (FXa). TFPI Kunitz domain 3 residue Glu226 is essential for enhancement of TFPI by protein S. To investigate the complementary functional interaction site on protein S, we screened 44 protein S point, composite or domain swap variants spanning the whole protein S molecule for their TFPI cofactor function using a thrombin generation assay. Of these variants, two protein S/growth arrestspecific 6 chimeras, with either the whole sex hormone-binding globulin (SHBG)-like domain (Val243-Ser635; chimera III) or the SHBG laminin G-type 1 subunit (Ser283-Val459; chimera I), respectively, substituted by the corresponding domain in growth arrest-specific 6, were unable to enhance TFPI. The importance of the protein S SHBG-like domain (and its laminin G-type 1 subunit) for binding and enhancement of TFPI was confirmed in FXa inhibition assays and using surface plasmon resonance. In addition, protein S bound to C4b binding protein showed greatly reduced enhancement of TFPI-mediated inhibition of FXa compared with free protein S. We show that binding of TFPI to the protein S SHBG-like domain enables TFPI to interact optimally with FXa on a phospholipid membrane. (Blood. 2014;123(25):3979-3987) IntroductionTissue factor pathway inhibitor (TFPI) is a ;41 kDa Kunitz-type protease inhibitor that consists of an acidic amino-terminal polypeptide, followed by 3 tandem Kunitz-type domains (Kunitz domains 1, 2, and 3) and a basic carboxy (C)-terminal tail. 1 It circulates in plasma at a concentration of ;1.6 nM. 2,3 The majority (;80%) of plasma TFPI is truncated and bound to lipoproteins, ;5% is localized in storage granules within platelets, ;5% circulates as free truncated variants, and only around 10% is considered to be free full-length TFPI, 4 with this having the greatest anticoagulant activity. [5][6][7] TFPI and its cofactor protein S downregulate tissue factor (TF)-induced thrombin generation, and a deficiency of either protein has been linked to an increased risk of venous thrombosis. [8][9][10] TFPI specifically inhibits the initiation of coagulation through direct binding and inhibition of factor Xa (FXa) and, in a FXa-dependent manner, inhibition of the TF/factor VIIa (FVIIa) complex by forming a quarternary TF/FVIIa/FXa/TFPI complex. 11,12 The P1 residue in the Kunitz domain 2 of TFPI is required for binding to FXa, whereas the P1 residue in Kunitz domain 1 is required for binding and inhibition of TF/FVIIa. 13 The kinetic mechanism of FXa inhibition by TFPI is described as a 2-step process where TFPI first forms an immediate encounter complex with FXa (FXa/TFPI), followed by a slow isomerization into a final tight complex (FXa/TFPI*...

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Section: Tfpi Cofactor Function Of Protein S 3985mentioning

confidence: 65%

Section: Discussionmentioning

confidence: 99%

TFPI cofactor function of protein S: essential role of the protein S SHBG-like domain

Reglińska-Matveyev

Andersson

Rezende

et al. 2014

Blood

Self Cite

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“…Calcium may affect the interaction of PS with C4BP either directly by binding an acidic C4BP residue or indirectly by stabilizing a PS conformation with high affinity for C4BP. In this regard, regions near the LG domain interface of PS have been implicated in C4BP binding (24).…”

Section: Discussionmentioning

confidence: 99%

“…Pink filled circles indicate calcium ligands. The underlined sequence in PS (residues His 453 -Ser 560 ) is involved in binding C4b-binding protein (24). Figs.…”

Section: Fig 1 the Gas6-lg Structurementioning

confidence: 99%

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Crystal Structure of a C-terminal Fragment of Growth Arrest-specific Protein Gas6

Sasaki

Knyazev

Cheburkin

et al. 2002

Journal of Biological Chemistry

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Receptor tyrosine kinases of the Axl family are activated by Gas6, the product of growth arrest-specific gene 6. Gas6-Axl signaling is implicated in cell survival, adhesion, and migration. The receptor-binding site of Gas6 is located within a C-terminal pair of laminin Glike (LG) domains that do not resemble any other receptor tyrosine kinase ligand. We report the crystal structure at 2.2-Å resolution of a Gas6 fragment spanning both LG domains (Gas6-LG). The structure reveals a V-shaped arrangement of LG domains strengthened by an interdomain calcium-binding site.LG2 of Gas6-LG contains two unusual features: an ␣-helix cradled by one edge of the LG ␤-sandwich and a conspicuous patch of surface-exposed hydrophobic residues. Mutagenesis of some residues in this patch reduces Gas6-LG binding to the extracellular domain of Axl as well as Axl activation in glioblastoma cells, identifying a component of the receptor-binding site of Gas6.

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A survey of the year 2002 commercial optical biosensor literature

Rich

Myszka

2003

J of Molecular Recognition

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We have compiled 819 articles published in the year 2002 that involved commercial optical biosensor technology. The literature demonstrates that the technology's application continues to increase as biosensors are contributing to diverse scientific fields and are used to examine interactions ranging in size from small molecules to whole cells. Also, the variety of available commercial biosensor platforms is increasing and the expertise of users is improving. In this review, we use the literature to focus on the basic types of biosensor experiments, including kinetics, equilibrium analysis, solution competition, active concentration determination and screening. In addition, using examples of particularly well-performed analyses, we illustrate the high information content available in the primary response data and emphasize the impact of including figures in publications to support the results of biosensor analyses.

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Structural Requirements of Anticoagulant Protein S for Its Binding to the Complement Regulator C4b-binding Protein

Cited by 27 publications

References 53 publications

TFPI cofactor function of protein S: essential role of the protein S SHBG-like domain

TFPI cofactor function of protein S: essential role of the protein S SHBG-like domain

Crystal Structure of a C-terminal Fragment of Growth Arrest-specific Protein Gas6

A survey of the year 2002 commercial optical biosensor literature

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