Part:BBa_K4165204
PHF (Paired Helical Filament)
Insoluble fibers Paired Helical filaments that accumulate id Alzheimer's disease and the other tauopathies.
Usage and Biology
Tau,a microtubule-binding protein, aggregates on itself, decreasing its functionality and being closely linked totauopathies, disorders that are tau-related. Tau aggregation is also closely linked to PHF6 (VQIVYK) and PHF*, two nucleating six-residue segments (VQIINK). Our part, VQIVYK, representing residues 306 to 311 of the tau, is crucial for the full-length protein to form fibrils, and it can also do it on its own. A short sequence motif called PHF6, which may be found near the start of the third internal repeat is necessary for the assembly of tau protein into paired helical filaments (PHFs). This motif's location determines how the protein will form. The most substantial predicted-structure potential in tau is congruent with this motif. Depending on the change in propensity, point mutations in the hexapeptide region can either reduce or increase aggregation. We chose this part as a therapeutic target for AD disease by blocking an additional layer of it.
Dry Lab Work
Figure 1.: RCSB Structure of PHF
Sequence and Features
- 10COMPATIBLE WITH RFC[10]
- 12COMPATIBLE WITH RFC[12]
- 21COMPATIBLE WITH RFC[21]
- 23COMPATIBLE WITH RFC[23]
- 25COMPATIBLE WITH RFC[25]
- 1000COMPATIBLE WITH RFC[1000]
References
1- Dammers, C., Yolcu, D., Kukuk, L., Willbold, D., Pickhardt, M., & Mandelkow, E. et al. (2016). Selection and Characterization of Tau Binding ᴅ-Enantiomeric Peptides with Potential for Therapy of Alzheimer Disease. PLOS ONE, 11(12), e0167432. doi: 10.1371/journal.pone.0167432
2- Barghorn, S., Davies, P., & Mandelkow, E. (2004). Tau Paired Helical Filaments from Alzheimer's Disease Brain and Assembled in Vitro Are Based on β-Structure in the Core Domain. Biochemistry, 43(6), 1694-1703. doi: 10.1021/bi0357006
3- von Bergen, M., Barghorn, S., Li, L., Marx, A., Biernat, J., Mandelkow, E., & Mandelkow, E. (2001). Mutations of Tau Protein in Frontotemporal Dementia Promote Aggregation of Paired Helical Filaments by Enhancing Local β-Structure. Journal Of Biological Chemistry, 276(51), 48165-48174. doi: 10.1074/jbc.m105196200
4- Ganguly, P., Do, T., Larini, L., LaPointe, N., Sercel, A., & Shade, M. et al. (2015). Tau Assembly: The Dominant Role of PHF6 (VQIVYK) in Microtubule Binding Region Repeat R3. The Journal Of Physical Chemistry B, 119(13), 4582-4593. doi: 10.1021/acs.jpcb.5b00175
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