The conformations of filamentous and soluble tau associated with Alzheimer paired helical filaments.
Paired helical filaments (PHF) occur in Alzheimer's diseased brains and are known to be composed of the microtubule-associated protein, tau. In the present report, circular dichroism (CD) spectroscopy and transmission electron microscopy (TEM) were used to characterize PHF suspended in Tris-buffered saline (TBS), sodium acetate buffer, and water. In TBS the CD spectrum of PHF was observed to have a spectral pattern consistent with 31-37% alpha-helix, 15-20% beta-sheet, 20-23% turn, and 26-29% unordered structure. The TBS sample was found to undergo a cooperative thermal transition between 70 and 75 degrees C, consistent with the changes observed in filament morphology, and it suggests that filamentous tau in the PHF (PHF-tau) makes a substantial contribution to the overall CD. Observed changes in the CD spectrum following removal of PHF by centrifugation suggest that PHF-tau possesses a higher fraction of alpha-helical structure than soluble tau. In acetate buffer, where only straight filaments were observed, the CD was consistent with a marked decrease in the fraction of alpha-helix and an increase in the fraction of beta-sheet relative to the sample in TBS. In water, where only rudimentary filaments remain, the CD was consistent with a Type II or II' beta-turn conformation. Only noncooperative thermal transitions were observed for the PHF samples in acetate buffer and water, consistent with the presence of a heterogeneous population of folded structures. Taken cumulatively, the results are consistent with immunological data showing the presence of folded forms of tau and suggest that phosphorylation or nonproteinaceous components are able to induce conformations of tau other than the random coil conformation previously reported for cloned or purified human tau.
Goux
Warren J
WJ
Department of Chemistry, The University of Texas at Dallas, P.O. Box 830688, Richardson, Texas 75080, USA. wgoux@utdallas.edu
D000544:Alzheimer Disease / Q000473:pathology*; D002942:Circular Dichroism; D006801:Humans; D017348:Microscopy, Electron, Scanning Transmission; D008870:Microtubules / Q000737:chemistry; D008968:Molecular Conformation; D016874:Neurofibrillary Tangles / Q000378:metabolism / Q000648:ultrastructure; D016875:tau Proteins / Q000737:chemistry* / Q000378:metabolism / Q000648:ultrastructure
D016875:tau Proteins