Structural Polymorphism of 441-Residue Tau at Single Residue Resolution
By Marco D. Mukrasch, Stefan Bibow, Jegannath Korukottu, S. Jeganathan, J. Biernat, C. Griesinger, E. Mandelkow, M. Zweckstetter. PLoS Biology, 2009
624 citations recorded by the source corpus.
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 β-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.
Subfields: Cell Biology, Molecular Biology, Physiology
View Paper: https://www.semanticscholar.org/paper/e4dca691a3b8e64ea650227226f1bd573c53e8d6
How researchers see this paper
The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.
In Cell Biology
In Molecular Biology
In Physiology
Citations in the corpus
- Tau protein liquid–liquid phase separation can initiate tau aggregation (2018, neutral): “The disordered N-terminal projection domain [(Mukrasch et al , 2009); harbors short serine-and proline-rich domains of low amino acid complexity (Appendix Fig S1B), which may contribute to tau LLPS behavior.”
- Biochemistry and cell biology of tau protein in neurofibrillary degeneration. (2012, background): “dichroism, NMR and small angle X-ray scattering [SAXS]) show that the entire Tau molecule is “natively unfolded” or “intrinsically disordered” (Schweers et al. 1994; Mukrasch et al. 2009).”