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PDBsum entry 6epd
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Contents |
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246 a.a.
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234 a.a.
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249 a.a.
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246 a.a.
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233 a.a.
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238 a.a.
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245 a.a.
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202 a.a.
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219 a.a.
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205 a.a.
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196 a.a.
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201 a.a.
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213 a.a.
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216 a.a.
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195 a.a.
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289 a.a.
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263 a.a.
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24 a.a.
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896 a.a.
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905 a.a.
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476 a.a.
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456 a.a.
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422 a.a.
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389 a.a.
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288 a.a.
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376 a.a.
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396 a.a.
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385 a.a.
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391 a.a.
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389 a.a.
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415 a.a.
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406 a.a.
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References listed in PDB file
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Key reference
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Title
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In situ structure of neuronal c9orf72 poly-Ga aggregates reveals proteasome recruitment.
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Authors
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Q.Guo,
C.Lehmer,
A.Martínez-Sánchez,
T.Rudack,
F.Beck,
H.Hartmann,
M.Pérez-Berlanga,
F.Frottin,
M.S.Hipp,
F.U.Hartl,
D.Edbauer,
W.Baumeister,
R.Fernández-Busnadiego.
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Ref.
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Cell, 2018,
172,
696.
[DOI no: ]
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PubMed id
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Note: In the PDB file this reference is
annotated as "TO BE PUBLISHED". The citation details given above have
been manually determined.
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Abstract
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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.
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