期刊
JOURNAL OF BIOLOGICAL CHEMISTRY
卷 293, 期 45, 页码 17336-17348出版社
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.RA118.005316
关键词
Tau protein (Tau); amyloid; conformational change; Alzheimer disease; tauopathy; electron paramagnetic resonance (EPR); fibril; protein aggregation; prion; protein structure; seeding barrier
资金
- Federal funds from the Frederick National Laboratory for Cancer Research, National Institutes of Health [HHSN261200800001E]
- Intramural Research Program of National Institutes of Health, Frederick National Lab, Center for Cancer Research
- NATIONAL CANCER INSTITUTE [ZIABC010440] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE ON AGING [R21AG051833] Funding Source: NIH RePORTER
The intracellular deposition of fibrils composed of the microtubule-associated protein Tau is a characteristic feature of Alzheimer's disease (AD) and other fatal neurodegenerative disorders collectively known as tauopathies. Short Tau fibrils spread intracerebrally through transfer between interconnected neurons. Once taken up by a recipient cell, Tau fibrils recruit Tau monomers onto their ends. Based on the number of microtubule-binding repeats, there are two distinct groups of Tau isoforms: three-repeat (3R) Tau and four-repeat (4R) Tau. In AD, all Tau isoforms are deposited, whereas in other tauopathies, only 3R or 4R Tau isoforms are deposited. The molecular basis for these isoform-specific depositions is poorly understood, although conformation-based cross-seeding barriers are key. Here, we used sedimentation assays, EPR spectroscopy, and other structural readouts to better understand the cross-seeding barriers of 4R Tau fibrils. We observed that fibrils formed from truncated Tau (K18), but not full-length Tau (htau40), exhibit a barrier that inhibits 3R Tau recruitment. Investigating an array of differently sized fragments, we found that the Tau C terminus modulates the cross-seeding barrier and that the N terminus plays a synergistic role. Two disease-associated Tau variants, P301S and P301L, also established strong cross-seeding barriers. EPR analysis indicated that fibrils seeded with truncated and mutated Tau, but not htau40, are structurally disordered in the second half of repeat four and onward. These findings suggest that the disorder in this region diminishes the ability of 4R Tau fibrils to recruit 3R Tau monomers, revealing a new mechanism for Tau cross-seeding barriers.
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