Structural insights into Alzheimer filament assembly pathways based on site-directed mutagenesis and S-glutathionylation of three-repeat neuronal Tau protein.
Although Tau and MAP2 readily assemble into straight filaments (SFs), Tau's unique ability to form paired-helical filaments (PHFs) may offer clues as to why Tau's microtubule-binding region (MTBR) is the exclusive building block of the neurofibrillary tangles that accumulate during Alzheimer's disease. To learn more about the factors permitting Tau to form both SFs and PHFs, we investigated the microtubule binding, thiol oxidation, and polymerization reactions of the monomer and dimer forms of Tau and MAP2 MTBRs. This review focuses on electron microscopic evidence (1) that facilitated the identification of amino acid residues within 3-repeat Tau that promote PHF formation; and (2) provided experimental evidence for the polymerization of S-glutathionylated three-repeat Tau, a reaction that unambiguously demonstrates that disulfide-linked Tau-S-S-Tau dimer formation is not a compulsory step in filament assembly. We also consider these findings within the context of current views on the genetic and biochemical basis of Tau fibrillogenesis.
Dinoto
Luca
L
Department of Biochemistry and Molecular Biology, University of Florida College of Medicine, Gainesville, Florida 32610-0245, USA.
Deture
Michael A
MA
Purich
Daniel L
DL
D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D000595:Amino Acid Sequence; D006801:Humans; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism / Q000648:ultrastructure*; D008870:Microtubules / Q000378:metabolism / Q000648:ultrastructure; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D016874:Neurofibrillary Tangles / Q000378:metabolism / Q000648:ultrastructure*; D010766:Phosphorylation; D011485:Protein Binding; D016875:tau Proteins / Q000235:genetics / Q000378:metabolism / Q000648:ultrastructure*
D008869:Microtubule-Associated Proteins; D016875:tau Proteins