title: Thermodynamics of the interaction between Alzheimer's disease related tau protein and DNA.
abstract: Tau hyperphosphorylation can be considered as one of the hallmarks of Alzheimer's disease and other tauophaties. Besides its well-known role as a microtubule associated protein, Tau displays a key function as a protector of genomic integrity in stress situations. Phosphorylation has been proven to regulate multiple processes including nuclear translocation of Tau. In this contribution, we are addressing the physicochemical nature of DNA-Tau interaction including the plausible influence of phosphorylation. By means of surface plasmon resonance (SPR) we measured the equilibrium constant and the free energy, enthalpy and entropy changes associated to the Tau-DNA complex formation. Our results show that unphosphorylated Tau binding to DNA is reversible. This fact is in agreement with the protective role attributed to nuclear Tau, which stops binding to DNA once the insult is over. According to our thermodynamic data, oscillations in the concentration of dephosphorylated Tau available to DNA must be the variable determining the extent of Tau binding and DNA protection. In addition, thermodynamics of the interaction suggest that hydrophobicity must represent an important contribution to the stability of the Tau-DNA complex. SPR results together with those from Tau expression in HEK cells show that phosphorylation induces changes in Tau protein which prevent it from binding to DNA. The phosphorylation-dependent regulation of DNA binding is analogous to the Tau-microtubules binding inhibition induced by phosphorylation. Our results suggest that hydrophobicity may control Tau location and DNA interaction and that impairment of this Tau-DNA interaction, due to Tau hyperphosphorylation, could contribute to Alzheimer's pathogenesis.
authors.affiliation: Departamento de Química Física Aplicada, Universidad Autónoma de Madrid, Madrid, Spain; Centro de Biología Molecular Severo Ochoa, Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid, (CSIC/UAM), Madrid, Spain.
authors.forename: Sergio
authors.initials: S
authors.lastname: Camero
authors.affiliation: Departamento de Química Física Aplicada, Universidad Autónoma de Madrid, Madrid, Spain; Centro de Biología Molecular Severo Ochoa, Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid, (CSIC/UAM), Madrid, Spain.
authors.forename: María J
authors.initials: MJ
authors.lastname: Benítez
authors.affiliation: Centro de Biología Molecular Severo Ochoa, Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid, (CSIC/UAM), Madrid, Spain.
authors.forename: Raquel
authors.initials: R
authors.lastname: Cuadros
authors.affiliation: Centro de Biología Molecular Severo Ochoa, Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid, (CSIC/UAM), Madrid, Spain; Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain.
authors.forename: Félix
authors.initials: F
authors.lastname: Hernández
authors.affiliation: Centro de Biología Molecular Severo Ochoa, Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid, (CSIC/UAM), Madrid, Spain; Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain.
authors.forename: Jesús
authors.initials: J
authors.lastname: Avila
authors.affiliation: Departamento de Química Física Aplicada, Universidad Autónoma de Madrid, Madrid, Spain.
authors.forename: Juan S
authors.initials: JS
authors.lastname: Jiménez
mesh_terms: D000544:Alzheimer Disease / Q000473:pathology; D002460:Cell Line; D004247:DNA / Q000235:genetics / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D010766:Phosphorylation; D020349:Surface Plasmon Resonance; D013816:Thermodynamics; D016875:tau Proteins / Q000378:metabolism*
chemical_list: D004268:DNA-Binding Proteins; C054369:MAPT protein, human; D016875:tau Proteins; D004247:DNA