8ONS

TAF15 amyloid fold in atypical FTLD - Individual 1

8ONS の概要

• エントリーDOI: 10.2210/pdb8ons/pdb
• EMDBエントリー: 16999
• 分子名称: TATA-binding protein-associated factor 2N (2 entities in total)
• 機能のキーワード: amyloid, amyloid-forming protein, neurodegeneration, rna binding protein
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 5
• 化学式量合計: 309545.00

構造登録者

Tetter, S.,Ryskeldi-Falcon, B. (登録日: 2023-04-03, 公開日: 2023-12-06, 最終更新日: 2024-02-07)

主引用文献

Tetter, S.,Arseni, D.,Murzin, A.G.,Buhidma, Y.,Peak-Chew, S.Y.,Garringer, H.J.,Newell, K.L.,Vidal, R.,Apostolova, L.G.,Lashley, T.,Ghetti, B.,Ryskeldi-Falcon, B.
TAF15 amyloid filaments in frontotemporal lobar degeneration.
Nature, 625:345-351, 2024

PubMed Abstract: Frontotemporal lobar degeneration (FTLD) causes frontotemporal dementia (FTD), the most common form of dementia after Alzheimer's disease, and is often also associated with motor disorders. The pathological hallmarks of FTLD are neuronal inclusions of specific, abnormally assembled proteins. In the majority of cases the inclusions contain amyloid filament assemblies of TAR DNA-binding protein 43 (TDP-43) or tau, with distinct filament structures characterizing different FTLD subtypes. The presence of amyloid filaments and their identities and structures in the remaining approximately 10% of FTLD cases are unknown but are widely believed to be composed of the protein fused in sarcoma (FUS, also known as translocated in liposarcoma). As such, these cases are commonly referred to as FTLD-FUS. Here we used cryogenic electron microscopy (cryo-EM) to determine the structures of amyloid filaments extracted from the prefrontal and temporal cortices of four individuals with FTLD-FUS. Surprisingly, we found abundant amyloid filaments of the FUS homologue TATA-binding protein-associated factor 15 (TAF15, also known as TATA-binding protein-associated factor 2N) rather than of FUS itself. The filament fold is formed from residues 7-99 in the low-complexity domain (LCD) of TAF15 and was identical between individuals. Furthermore, we found TAF15 filaments with the same fold in the motor cortex and brainstem of two of the individuals, both showing upper and lower motor neuron pathology. The formation of TAF15 amyloid filaments with a characteristic fold in FTLD establishes TAF15 proteinopathy in neurodegenerative disease. The structure of TAF15 amyloid filaments provides a basis for the development of model systems of neurodegenerative disease, as well as for the design of diagnostic and therapeutic tools targeting TAF15 proteinopathy.

PubMed: 38057661
DOI: 10.1038/s41586-023-06801-2

実験手法

ELECTRON MICROSCOPY (1.97 Å)