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J. Biol. Chem., Vol. 276, Issue 51, 48165-48174, December 21, 2001
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From the ¶ Max-Planck-Unit for Structural Molecular Biology,
Notkestrasse 85, 22607 Hamburg, Germany
The microtubule-associated protein tau is a
natively unfolded protein in solution, yet it is able to polymerize
into the ordered paired helical filaments (PHF) of Alzheimer's
disease. In the splice isoforms lacking exon 10, this process is
facilitated by the formation of
Mutations of Tau Protein in Frontotemporal Dementia
Promote Aggregation of Paired Helical Filaments by Enhancing Local
-Structure*
§,¶,
-structure around the hexapeptide
motif PHF6 (306VQIVYK311) encoded
by exon 11. We have investigated the structural requirements for PHF
polymerization in the context of adult tau isoforms containing four
repeats (including exon 10). In addition to the PHF6 motif there exists
a related PHF6* motif (275VQIINK280) in the
repeat encoded by the alternatively spliced exon 10. We show that this
PHF6* motif also promotes aggregation by the formation of -structure
and that there is a cross-talk between the two hexapeptide motifs
during PHF aggregation. We also show that two of the tau mutations
found in hereditary frontotemporal dementias, 
K280 and P301L, have a
much stronger tendency for PHF aggregation which correlates with their
high propensity for -structure around the hexapeptide motifs.
*
This work was supported by a grant from the Deutsche
Forschungsgemeinschaft.The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
Both authors contributed equally to this work.
§
Present address: Mice & More GmbH & Co. KG, Falkenried 88, 20251 Hamburg.
To whom correspondence should be addressed:
Max-Planck-Unit for Structural Molecular Biology, Notkestrasse 85, 22607 Hamburg. Tel.: 49-40-8998-2810; Fax: 49-40-8971-6810; E-mail:
mand@mpasmb.desy.de.
Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.
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