Fibers of tau fragments, but not full length tau, exhibit a cross beta-structure: implications for the formation of paired helical filaments.
We have used X-ray fiber diffraction to probe the structure of fibers of tau and tau fragments. Fibers of fragments from the microtubule binding domain had a cross beta-structure that closely resembles that reported both for neurofibrillary tangles found in Alzheimer's disease brain and for fibrous lesions from other protein folding diseases. In contrast, fibers of full-length tau had a different, more complex structure. Despite major differences at the molecular level, all fiber types exhibited very similar morphology by electron microscopy. These results have a number of implications for understanding the etiology of Alzheimer's and other tauopathic diseases. The morphology of the peptide fibers suggests that the region in tau corresponding to the peptides plays a critical role in the nucleation of fiber assembly. The dramatically different structure of the full length tau fibers suggests that some region in tau has enough inherent structure to interfere with the formation of cross beta-fibers. Additionally, the similar appearance by electron microscopy of fibrils with varying molecular structure suggests that different molecular arrangements may exist in other samples of fibers formed from tau.
Giannetti
A M
AM
Program in Biochemistry, California Institute of Technology, University of California, Santa Barbara 93106, USA.
Lindwall
G
G
Chau
M F
MF
Radeke
M J
MJ
Feinstein
S C
SC
Kohlstaedt
L A
LA
D000544:Alzheimer Disease / Q000209:etiology; D001665:Binding Sites; D006801:Humans; D008854:Microscopy, Electron; D008870:Microtubules / Q000378:metabolism; D016874:Neurofibrillary Tangles; D010446:Peptide Fragments / Q000138:chemical synthesis / Q000737:chemistry; D020033:Protein Isoforms / Q000737:chemistry; D017433:Protein Structure, Secondary; D014961:X-Ray Diffraction; D016875:tau Proteins / Q000737:chemistry* / Q000648:ultrastructure
D010446:Peptide Fragments; D020033:Protein Isoforms; D016875:tau Proteins