DNA binds to a specific site of the adhesive blood-protein von Willebrand factor guided by electrostatic interactions
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DNA binds to a specific site of the adhesive blood-protein von Willebrand factor guided by electrostatic interactions. / Sandoval-Pérez, Angélica; Berger, Ricarda M L; Garaizar, Adiran; Farr, Stephen E; Brehm, Maria A; König, Gesa; Schneider, Stefan W; Collepardo-Guevara, Rosana; Huck, Volker; Rädler, Joachim O; Aponte-Santamaría, Camilo.
In: NUCLEIC ACIDS RES, Vol. 48, No. 13, 27.07.2020, p. 7333-7344.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - DNA binds to a specific site of the adhesive blood-protein von Willebrand factor guided by electrostatic interactions
AU - Sandoval-Pérez, Angélica
AU - Berger, Ricarda M L
AU - Garaizar, Adiran
AU - Farr, Stephen E
AU - Brehm, Maria A
AU - König, Gesa
AU - Schneider, Stefan W
AU - Collepardo-Guevara, Rosana
AU - Huck, Volker
AU - Rädler, Joachim O
AU - Aponte-Santamaría, Camilo
N1 - © The Author(s) 2020. Published by Oxford University Press on behalf of Nucleic Acids Research.
PY - 2020/7/27
Y1 - 2020/7/27
N2 - Neutrophils release their intracellular content, DNA included, into the bloodstream to form neutrophil extracellular traps (NETs) that confine and kill circulating pathogens. The mechanosensitive adhesive blood protein, von Willebrand Factor (vWF), interacts with the extracellular DNA of NETs to potentially immobilize them during inflammatory and coagulatory conditions. Here, we elucidate the previously unknown molecular mechanism governing the DNA-vWF interaction by integrating atomistic, coarse-grained, and Brownian dynamics simulations, with thermophoresis, gel electrophoresis, fluorescence correlation spectroscopy (FCS), and microfluidic experiments. We demonstrate that, independently of its nucleotide sequence, double-stranded DNA binds to a specific helix of the vWF A1 domain, via three arginines. This interaction is attenuated by increasing the ionic strength. Our FCS and microfluidic measurements also highlight the key role shear-stress has in enabling this interaction. Our simulations attribute the previously-observed platelet-recruitment reduction and heparin-size modulation, upon establishment of DNA-vWF interactions, to indirect steric hindrance and partial overlap of the binding sites, respectively. Overall, we suggest electrostatics-guiding DNA to a specific protein binding site-as the main driving force defining DNA-vWF recognition. The molecular picture of a key shear-mediated DNA-protein interaction is provided here and it constitutes the basis for understanding NETs-mediated immune and hemostatic responses.
AB - Neutrophils release their intracellular content, DNA included, into the bloodstream to form neutrophil extracellular traps (NETs) that confine and kill circulating pathogens. The mechanosensitive adhesive blood protein, von Willebrand Factor (vWF), interacts with the extracellular DNA of NETs to potentially immobilize them during inflammatory and coagulatory conditions. Here, we elucidate the previously unknown molecular mechanism governing the DNA-vWF interaction by integrating atomistic, coarse-grained, and Brownian dynamics simulations, with thermophoresis, gel electrophoresis, fluorescence correlation spectroscopy (FCS), and microfluidic experiments. We demonstrate that, independently of its nucleotide sequence, double-stranded DNA binds to a specific helix of the vWF A1 domain, via three arginines. This interaction is attenuated by increasing the ionic strength. Our FCS and microfluidic measurements also highlight the key role shear-stress has in enabling this interaction. Our simulations attribute the previously-observed platelet-recruitment reduction and heparin-size modulation, upon establishment of DNA-vWF interactions, to indirect steric hindrance and partial overlap of the binding sites, respectively. Overall, we suggest electrostatics-guiding DNA to a specific protein binding site-as the main driving force defining DNA-vWF recognition. The molecular picture of a key shear-mediated DNA-protein interaction is provided here and it constitutes the basis for understanding NETs-mediated immune and hemostatic responses.
U2 - 10.1093/nar/gkaa466
DO - 10.1093/nar/gkaa466
M3 - SCORING: Journal article
C2 - 32496552
VL - 48
SP - 7333
EP - 7344
JO - NUCLEIC ACIDS RES
JF - NUCLEIC ACIDS RES
SN - 0305-1048
IS - 13
ER -