Structure, microtubule interactions, and paired helical filament aggregation by tau mutants of frontotemporal dementias.
We have studied biochemical and structural parameters of several missense and deletion mutants of tau protein (G272V, N279K, DeltaK280, P301L, V337M, R406W) found in frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17). The mutant proteins were expressed on the basis of both full-length tau (htau40) and constructs derived from the repeat domain. They were analyzed with respect to the capacity to enhance microtubule assembly, binding of tau to microtubules, secondary structure content, and aggregation into Alzheimer-like paired helical or straight filaments. We find that the mutations cause a moderate decrease in microtubule interactions and stabilization, and they show no gross structural changes compared with the natively unfolded conformation of the wild-type protein, but the aggregation into PHFs is strongly enhanced, particularly for the mutants DeltaK280 and P301L. This gain of pathological aggregation would be consistent with the autosomal dominant nature of the disease.
Barghorn
S
S
Max-Planck-Unit for Structural Molecular Biology, c/o DESY, Notkestrasse 85, D-22607 Hamburg, Germany.
Zheng-Fischhöfer
Q
Q
Ackmann
M
M
Biernat
J
J
von Bergen
M
M
Mandelkow
E M
EM
Mandelkow
E
E
D008841:Actin Cytoskeleton / Q000737:chemistry / Q000235:genetics / Q000378:metabolism* / Q000648:ultrastructure; D052160:Benzothiazoles; D002942:Circular Dichroism; D003704:Dementia / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D008854:Microscopy, Electron; D008870:Microtubules / Q000737:chemistry / Q000235:genetics / Q000378:metabolism* / Q000648:ultrastructure; D016297:Mutagenesis, Site-Directed; D009154:Mutation; D020125:Mutation, Missense; D019600:Neuropil Threads / Q000235:genetics / Q000378:metabolism / Q000648:ultrastructure; D017239:Paclitaxel / Q000737:chemistry; D011485:Protein Binding / Q000235:genetics; D017433:Protein Structure, Secondary / Q000235:genetics; D012542:Scattering, Radiation; D017384:Sequence Deletion; D013050:Spectrometry, Fluorescence; D013844:Thiazoles / Q000737:chemistry; D016875:tau Proteins / Q000737:chemistry* / Q000235:genetics* / Q000378:metabolism / Q000648:ultrastructure
D052160:Benzothiazoles; D013844:Thiazoles; D016875:tau Proteins; C009462:thioflavin T; D017239:Paclitaxel