التفاصيل البيبلوغرافية
| العنوان: |
FTD-tau S320F mutation stabilizes local structure and allosterically promotes amyloid motif-dependent aggregation |
| المؤلفون: |
Dailu Chen, Sofia Bali, Ruhar Singh, Aleksandra Wosztyl, Vishruth Mullapudi, Jaime Vaquer-Alicea, Parvathy Jayan, Shamiram Melhem, Harro Seelaar, John C. Swieten, Marc I. Diamond, Lukasz A. |
| المصدر: |
Nature, Nature Communications. 14(1):1-17 |
| سنة النشر: |
2023 |
| الوصف: |
Amyloid deposition of the microtubule-associated protein tau is associated with neurodegenerative diseases. In frontotemporal dementia with abnormal tau (FTD-tau), missense mutations in tau enhance its aggregation propensity. Here we describe the structural mechanism for how an FTD-tau S320F mutation drives spontaneous aggregation, integrating data from in vitro, in silico and cellular experiments. We find that S320F stabilizes a local hydrophobic cluster which allosterically exposes the 306VQIVYK311 amyloid motif; identify a suppressor mutation that destabilizes S320F-based hydrophobic clustering reversing the phenotype in vitro and in cells; and computationally engineer spontaneously aggregating tau sequences through optimizing nonpolar clusters surrounding the S320 position. We uncover a mechanism for regulating tau aggregation which balances local nonpolar contacts with long-range interactions that sequester amyloid motifs. Understanding this process may permit control of tau aggregation into structural polymorphs to aid the design of reagents targeting disease-specific tau conformations. |
| نوع الوثيقة: |
redif-article |
| اللغة: |
English |
| DOI: |
10.1038/s41467-023-37274 |
| الإتاحة: |
https://ideas.repec.org/a/nat/natcom/v14y2023i1d10.1038_s41467-023-37274-6.html |
| رقم الأكسشن: |
edsrep.a.nat.natcom.v14y2023i1d10.1038.s41467.023.37274.6 |
| قاعدة البيانات: |
RePEc |
