14-3-3zeta is an effector of tau protein phosphorylation.
Neurofibrillary tangles associated with Alzheimer's disease are composed mainly of paired helical filaments that are formed by the aggregation of abnormally phosphorylated microtubule-associated protein tau. 14-3-3, a highly conserved protein family that exists as seven isoforms and regulates diverse cellular processes is present in neurofibrillary tangles (Layfield, R., Fergusson, J., Aitken, A., Lowe, J., Landon, M., Mayer, R. J. (1996) Neurosci. Lett. 209, 57-60). The role of 14-3-3 in Alzheimer's disease pathogenesis is not known. In this study, we found that the 14-3-3zeta isoform is associated with tau in brain extract and profoundly stimulates cAMP-dependent protein kinase catalyzed in vitro phosphorylation on Ser(262)/Ser(356) located within the microtubule-binding region of tau. 14-3-3zeta binds to both phosphorylated and nonphosphorylated tau, and the binding site is located within the microtubule-binding region of tau. From brain extract, 14-3-3zeta co-purifies with microtubules, and tubulin blocks 14-3-3zeta-tau binding. Among four 14-3-3 isoforms tested, beta and zeta but not gamma and epsilon associate with tau. Our data suggest that 14-3-3zeta is a tau protein effector and may be involved in the abnormal tau phosphorylation occurring during Alzheimer's disease ontogeny.
Hashiguchi
M
M
Bloomfield Center for Research in Aging, Lady Davis Institute for Medical Research, Sir Mortimer B. Davis-Jewish General Hospital, Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec, Canada.
Sobue
K
K
Paudel
H K
HK
D048948:14-3-3 Proteins; D000544:Alzheimer Disease; D000911:Antibodies, Monoclonal / Q000378:metabolism; D001665:Binding Sites; D001921:Brain / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004591:Electrophoresis, Polyacrylamide Gel; D017353:Gene Deletion; D005982:Glutathione Transferase / Q000378:metabolism; D006801:Humans; D015151:Immunoblotting; D008870:Microtubules / Q000378:metabolism; D016296:Mutagenesis; D010766:Phosphorylation; D010957:Plasmids / Q000378:metabolism; D011233:Precipitin Tests; D020033:Protein Isoforms; D011506:Proteins / Q000737:chemistry / Q000378:metabolism / Q000502:physiology*; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D012694:Serine / Q000737:chemistry; D014404:Tubulin / Q000494:pharmacology; D014446:Tyrosine 3-Monooxygenase; D016875:tau Proteins / Q000737:chemistry / Q000378:metabolism*
D048948:14-3-3 Proteins; D000911:Antibodies, Monoclonal; D020033:Protein Isoforms; D011506:Proteins; D011993:Recombinant Fusion Proteins; D014404:Tubulin; D016875:tau Proteins; D012694:Serine; D014446:Tyrosine 3-Monooxygenase; D005982:Glutathione Transferase; D017868:Cyclic AMP-Dependent Protein Kinases