Structural polymorphism of 441-residue tau at single residue resolution.
Alzheimer disease is characterized by abnormal protein deposits in the brain, such as extracellular amyloid plaques and intracellular neurofibrillary tangles. The tangles are made of a protein called tau comprising 441 residues in its longest isoform. Tau belongs to the class of natively unfolded proteins, binds to and stabilizes microtubules, and partially folds into an ordered beta-structure during aggregation to Alzheimer paired helical filaments (PHFs). Here we show that it is possible to overcome the size limitations that have traditionally hampered detailed nuclear magnetic resonance (NMR) spectroscopy studies of such large nonglobular proteins. This is achieved using optimal NMR pulse sequences and matching of chemical shifts from smaller segments in a divide and conquer strategy. The methodology reveals that 441-residue tau is highly dynamic in solution with a distinct domain character and an intricate network of transient long-range contacts important for pathogenic aggregation. Moreover, the single-residue view provided by the NMR analysis reveals unique insights into the interaction of tau with microtubules. Our results establish that NMR spectroscopy can provide detailed insight into the structural polymorphism of very large nonglobular proteins.
Mukrasch
Marco D
MD
Department for Nuclear Magnetic Resonance (NMR)-Based Structural Biology, Max Planck Institute for Biophysical Chemistry, Göttingen, Germany.
Bibow
Stefan
S
Korukottu
Jegannath
J
Jeganathan
Sadasivam
S
Biernat
Jacek
J
Griesinger
Christian
C
Mandelkow
Eckhard
E
Zweckstetter
Markus
M
D000544:Alzheimer Disease / Q000235:genetics* / Q000378:metabolism; D000595:Amino Acid Sequence; D000818:Animals; D001369:Axons / Q000378:metabolism; D006801:Humans; D008870:Microtubules / Q000737:chemistry / Q000378:metabolism; D008969:Molecular Sequence Data; D016874:Neurofibrillary Tangles / Q000235:genetics / Q000378:metabolism; D019906:Nuclear Magnetic Resonance, Biomolecular / Q000379:methods; D011487:Protein Conformation; D017510:Protein Folding; D020033:Protein Isoforms; D017433:Protein Structure, Secondary; D013552:Swine; D016875:tau Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism
C054369:MAPT protein, human; D020033:Protein Isoforms; D016875:tau Proteins