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Structure paper

タイトル	In Situ Structure of Neuronal C9orf72 Poly-GA Aggregates Reveals Proteasome Recruitment.
ジャーナル・号・ページ	Cell, Vol. 172, Issue 4, Page 696-705.e12, Year 2018
掲載日	2018年2月8日
著者	Qiang Guo / Carina Lehmer / Antonio Martínez-Sánchez / Till Rudack / Florian Beck / Hannelore Hartmann / Manuela Pérez-Berlanga / Frédéric Frottin / Mark S Hipp / F Ulrich Hartl / Dieter Edbauer / Wolfgang Baumeister / Rubén Fernández-Busnadiego /
PubMed 要旨	Protein aggregation and dysfunction of the ubiquitin-proteasome system are hallmarks of many neurodegenerative diseases. Here, we address the elusive link between these phenomena by employing cryo- ...Protein aggregation and dysfunction of the ubiquitin-proteasome system are hallmarks of many neurodegenerative diseases. Here, we address the elusive link between these phenomena by employing cryo-electron tomography to dissect the molecular architecture of protein aggregates within intact neurons at high resolution. We focus on the poly-Gly-Ala (poly-GA) aggregates resulting from aberrant translation of an expanded GGGGCC repeat in C9orf72, the most common genetic cause of amyotrophic lateral sclerosis and frontotemporal dementia. We find that poly-GA aggregates consist of densely packed twisted ribbons that recruit numerous 26S proteasome complexes, while other macromolecules are largely excluded. Proximity to poly-GA ribbons stabilizes a transient substrate-processing conformation of the 26S proteasome, suggesting stalled degradation. Thus, poly-GA aggregates may compromise neuronal proteostasis by driving the accumulation and functional impairment of a large fraction of cellular proteasomes.
リンク	Cell / PubMed:29398115 / PubMed Central
手法	EM (サブトモグラム平均) / EM (トモグラフィー)
解像度	11.8 - 17.1 Å
構造データ	3913 6epc EMDB-3913, PDB-6epc: Ground state 26S proteasome (GS2) 手法: EM (サブトモグラム平均) / 解像度: 12.3 Å 3914 6epd EMDB-3914, PDB-6epd: Substrate processing state 26S proteasome (SPS1) 手法: EM (サブトモグラム平均) / 解像度: 15.4 Å 3915 6epe EMDB-3915, PDB-6epe: Substrate processing state 26S proteasome (SPS2) 手法: EM (サブトモグラム平均) / 解像度: 12.8 Å 3916 6epf EMDB-3916, PDB-6epf: Ground state 26S proteasome (GS1) 手法: EM (サブトモグラム平均) / 解像度: 11.8 Å EMDB-3917: Rat TRiC structure 手法: EM (サブトモグラム平均) / 解像度: 17.1 Å EMDB-4191: In situ cryo-electron tomogram from Rat neuron with C9ORF72 Poly-GA aggregates 手法: EM (トモグラフィー)
由来	rattus norvegicus (ドブネズミ) Rat (クマネズミ属) Norway Rat (ドブネズミ)
キーワード	HYDROLASE (加水分解酵素) / UPS / Ground state (基底状態) / Neuron degeneration / Substrate processing state