+ Resolve Article
+ Follow Us
Follow on FacebookFollow on Facebook
Follow on TwitterFollow on Twitter

+ Translate
+ Subscribe to Site Feed
GeoScience Most Shared ContentMost Shared Content

β-Sheet core of tau paired helical filaments revealed by solid-state NMR

, : β-Sheet core of tau paired helical filaments revealed by solid-state NMR. Journal of the American Chemical Society 134(34): 13982-9

One of the hallmarks of Alzheimer's disease is the self-assembly of the microtubule-associated protein tau into fibers termed "paired helical filaments" (PHFs). However, the structural basis of PHF assembly at atomic detail is largely unknown. Here, we applied solid-state nuclear magnetic resonance (ssNMR) spectroscopy to investigate in vitro assembled PHFs from a truncated three-repeat tau isoform (K19) that represents the core of PHFs. We found that the rigid core of the fibrils is formed by amino acids V306 to S324, only 18 out of 99 residues, and comprises three β-strands connected by two short kinks. The first β-strand is formed by the well-studied hexapeptide motif VQIVYK that is known to self-aggregate in a steric zipper arrangement. Results on mixed [(15)N:(13)C]-labeled K19 fibrils show that β-strands are stacked in a parallel, in-register manner. Disulfide bridges formed between C322 residues of different molecules lead to a disturbance of the β-sheet structure, and polymorphism in ssNMR spectra is observed. In particular, residues K321-S324 exhibit two sets of resonances. Experiments on K19 C322A PHFs further confirm the influence of disulfide bond formation on the core structure. Our structural data are supported by H/D exchange NMR measurements on K19 as well as a truncated four-repeat isoform of tau (K18). Site-directed mutagenesis studies show that single-point mutations within the three different β-strands result in a significant loss of PHF aggregation efficiency, highlighting the importance of the β-structure-rich regions for tau aggregation.


PMID: 22862303

DOI: 10.1021/ja305470p

Other references

Langrehr, V.; Langrehr, F., 1989: Measuring the ability to repay: the residual income ratio. Journal of consumer affairser 23(2): 393-406

Stout, R.W., 1977: What is a general physician? His role in the teaching hospital. Ulster Medical Journal 46(2): 119-122

Chen, R.H.; Chameau, J. -L., 1983: Three-dimensional limit equilibrium analysis of slopes. Géotechnique 33(1): 31-40

Feldt-Rasmussen, B.; Nørgaard, K.; Jensen, T.; Mathiesen, E.; Deckert, T., 1990: The role of hypertension in the development of nephropathy in type 1 (insulin-dependent) diabetes mellitus. Which comes first when developing clinical diabetic nephropathy, the blood pressure rise or the increasing urinary albumin excretion? This issue is discussed based on recent literature of studies in humans with Type 1 (insulin-dependent) diabetes...

Stocks, C.; Barker, A.J.; Guy, S., 2002: The composting of brewery sludge. Sludge produced from a trickling filter effluent treatment plant dedicated to the treatment of brewery wastewater was flocculated with cationic polyelectrolytes and dewatered by centrifugation to produce a cake of around 16% (w/w) solids. This cak...

Wijman, C.A.C.; Mlynash, M.; Caulfield, A.Finley.; Hsia, A.W.; Eyngorn, I.; Bammer, R.; Fischbein, N.; Albers, G.W.; Moseley, M., 2009: Prognostic value of brain diffusion-weighted imaging after cardiac arrest. Outcome prediction is challenging in comatose postcardiac arrest survivors. We assessed the feasibility and prognostic utility of brain diffusion-weighted magnetic resonance imaging (DWI) during the first week. Consecutive comatose postcardiac arr...

Shields R.L.; Gold W.M., 1982: Effects of acute ozone exposure on lung histamine concentration. American Review of Respiratory Disease 125(4 PART 2): 148

McDowell, M.E.; Occhipinti, S.; Gardiner, R.A.; Baade, P.D.; Steginga, S.K., 2010: A review of prostate-specific antigen screening prevalence and risk perceptions for first-degree relatives of men with prostate cancer. First-degree relatives of men with prostate cancer have a higher risk of being diagnosed with prostate cancer than men without a family history. The present review examines the prevalence and predictors of testing in first-degree relatives, percep...

Cleary, J.P.; Hofmeister, J.; Fritz, M.; O'hara, E., 1998: Repeated aggregated Abeta injections treated with ibuprofen Behavior and CNS response in rats. Society for Neuroscience Abstracts 24(1-2): 731

Anonymous, 2001: Minutes of meeting: September 24-25, 1998. Human Gene Therapy 11(7): 1083-1109