Tau is a microtubule-associated protein that plays an important role in axonal stabilization, neuronal development, and neuronal polarity. In this review, we focus on the primary, secondary, tertiary, and quaternary tau structures. We describe the structure of tau from its specific residues until its conformation in dimers, oligomers, and larger polymers in physiological and pathological situations.
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.
ABSrRACTThe catalytic subunit of cyclic AMP-dependent protein kinase (from rabbit skeletal muscle; ATP:protein phosphotransferase, EC 2.7.1.37) was found to be irreversibly inactivated by chloromethyl ketone derivatives of lysine and phenylalanine, chentical reagents originally designed for labeling the active sites of the proteolytic enzymes trypsin and chymotrypsin. This inactivation was shown to occur at H 7.5 and 220C, conditions under which chemically relate alkylating reagents such as chloroacetamide and chloroacetic acid (which do not possess the amino acid side chain) fail to inactivate the enzyme. In the case of the chloromethyl ketone derivative of Na-tosylIL lysine, the enzyme could be protected by its nucleotide substrate (MgATP), by one of its protein substrates (histone H2b), and by its regulatory subunit which, upon binding, shields the active site of the catalytic subunit. Differential labeling experiments, together with kinetic studies of the rates of modification of the sulfhydryl groups in the enzyme before and after inactivation with the chloromethyl ketone, suggest that the loss of activity is associated with one (kinetically characterized) sulfhydryl group present either at the active site of the enye or at a site intimately associated with it. The general implications of these results regarding the interpretation of affinity labeling experiments carried out in complex mixtures of proteins or under in vivo conditions are discussed.
A number of neurodegenerative diseases, including Alzheimer's disease, tauopathies, Parkinson's disease, and synucleinopathies, polyglutamine diseases, including Huntington's disease, amyotrophic lateral sclerosis, and transmissible spongiform encephalopathy, are characterized by the existence of a protein or peptide prone to aggregation specific to the disease: amyloid-β, tau protein, α-synuclein, atrophin 1, androgen receptor, prion protein, copper-zinc superoxide dismutase, α 1A subunit of CaV2.1, TATA-box binding protein, huntingtin, and ataxins 1, 2, 3, and 7. Beside this common molecular feature, we have found three additional main properties related to the disease-connected protein or peptide, which are shared by all those neurological disorders: first, proneness to aggregation, which, in many cases, seems to be bound to the lack of a clearly defined secondary structure; second, reported presence of the disease-related protein inside the nucleus; and finally, an apparently unspecific interaction with DNA. These findings, together with the lack of clear details to explain the molecular origin of these neurodegenerative diseases, invite a hypothesis that, together with other plausible molecular explanations, may contribute to find the molecular basis of these diseases: I propose here the hypothesis that many neurological disorders may be the consequence, at least in part, of an aberrant interaction of the disease-related protein with nucleic acids, therefore affecting the normal DNA expression and giving place to a genetic stress which, in turn, alters the expression of proteins needed for the normal cellular function and regulation.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
customersupport@researchsolutions.com
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
This site is protected by reCAPTCHA and the Google Privacy Policy and Terms of Service apply.
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.