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The core of tau-paired helical filaments studied by scanning transmission electron microscopy and limited proteolysis

Von Bergen, M. and Barghorn, S. and Mueller, S. S. and Pickhardt, M. and Biernat, J. and Mandelkow, E. -M. and Davis, P. and Aebi, U. and Mandelkow, E.. (2006) The core of tau-paired helical filaments studied by scanning transmission electron microscopy and limited proteolysis. Biochemistry, Vol. 45, H. 20. pp. 6446-6457.

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Official URL: http://edoc.unibas.ch/dok/A5262475

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Abstract

In Alzheimer's disease and frontotemporal dementias the microtubule-associated protein tau forms intracellular paired helical filaments (PHFs). The filaments formed in vivo consist mainly of full-length molecules of the six different isoforms present in adult brain. The substructure of the PHF core is still elusive. Here we applied scanning transmission electron microscopy (STEM) and limited proteolysis to probe the mass distribution of PHFs and their surface exposure. Tau filaments assembled from the three repeat domain have a mass per length (MPL) of approximately 60 kDa/nm and filaments from full-length tau (htau40DeltaK280 mutant) have approximately 160 kDa/nm, compared with approximately 130 kDa/nm for PHFs from Alzheimer's brain. Polyanionic cofactors such as heparin accelerate assembly but are not incorporated into PHFs. Limited proteolysis combined with N-terminal sequencing and mass spectrometry of fragments reveals a protease-sensitive N-terminal half and semiresistant PHF core starting in the first repeat and reaching to the C-terminus of tau. Continued proteolysis leads to a fragment starting at the end of the first repeat and ending in the fourth repeat. PHFs from tau isoforms with four repeats revealed an additional cleavage site within the middle of the second repeat. Probing the PHFs with antibodies detecting epitopes either over longer stretches in the C-terminal half of tau or in the fourth repeat revealed that they grow in a polar manner. These data describe the physical parameters of the PHFs and enabled us to build a model of the molecular arrangement within the filamentous structures. [on SciFinder (R)]
Faculties and Departments:05 Faculty of Science > Departement Biozentrum > Former Organization Units Biozentrum > Structural Biology (Aebi)
UniBasel Contributors:Aebi, Ueli and M├╝ller, Shirley
Item Type:Article, refereed
Article Subtype:Research Article
Bibsysno:Link to catalogue
Publisher:American Chemical Society
ISSN:0006-2960
Note:Publication type according to Uni Basel Research Database: Journal article
Last Modified:22 Mar 2012 14:22
Deposited On:22 Mar 2012 13:30

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