Microtubule-associated Protein/Microtubule Affinity-regulating Kinase (p110
)
A NOVEL PROTEIN KINASE THAT REGULATES TAU-MICROTUBULE INTERACTIONS AND DYNAMIC INSTABILITY BY PHOSPHORYLATION AT THE ALZHEIMER-SPECIFIC SITE SERINE 262 (*)
- Gerard Drewes,
- Bernhard Trinczek,
- Susanne Illenberger,
- Jacek Biernat,
- Gerold Schmitt-Ulms,
- Helmut E. Meyer(1),
- Eva-Maria Mandelkow and
- Eckhard Mandelkow(§)
- From the Max-Planck Unit for Structural Molecular Biology, Notkestrasse 85, D-22603 Hamburg, Federal Republic of Germany and the Institut für Physiologische, Chemie, Ruhr-Universität, Universitätsstrasse 150, D-44780 Bochum, Federal Republic of Germany
- § To whom correspondence should be addressed: Tel.: 49-40-89982810; Fax: 49-40-891314; Mand{at}mpasmb.desy.de
Abstract
Aberrant phosphorylation of the microtubule-associated protein tau is one of the pathological features of neuronal degeneration in Alzheimer's disease. The phosphorylation of Ser-262 within the microtubule binding region of tau is of particular interest because so far it is observed only in Alzheimer's disease (Hasegawa, M., Morishima-Kawashima, M., Takio, K., Suzuki, M., Titani, K., and Ihara, Y.(1992) J. Biol. Chem. 26, 17047-17054) and because phosphorylation of this site alone dramatically reduces the affinity for microtubules in vitro (Biernat, J., Gustke, N., Drewes, G., Mandelkow, E.-M., and Mandelkow, E.(1993) Neuron 11, 153-163). Here we describe the purification and characterization of a protein-serine kinase from brain tissue with an apparent molecular mass of 110 kDa on SDS gels. This kinase specifically phosphorylates tau on its KIGS or KCGS motifs in the repeat domain, whereas no significant phosphorylation outside this region was detected. Phosphorylation occurs mainly on Ser-262 located in the first repeat. This largely abolishes tau's binding to microtubules and makes them dynamically unstable, in contrast to other protein kinases that phosphorylate tau at or near the repeat domain. The data suggest a role for this novel kinase in cellular events involving rearrangement of the microtubule-associated proteins/microtubule arrays and their pathological degeneration in Alzheimer's disease.
Footnotes
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↵* This project was supported by grants from BMFT and Deutsche Forschungsgemeinschaft and contains part of the Ph.D. thesis of S. I. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore by hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
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↵1 The abbreviations used are:
- MAP
-
microtubule-associated protein
- PHF
-
paired helical filament
- p110
-
MAP/microtubule affinity regulating kinase
- DTT
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dithiothreitol
- HPLC
-
high performance liquid chromatography
- MES
-
4-morpholineethanesulfonic acid
- Pipes
-
1,4-piperazinediethanesulfonic acid.
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- Received November 2, 1994.
- Revision received January 5, 1995.
- © 1995 by The American Society for Biochemistry and Molecular Biology, Inc.
