6EPE

Substrate processing state 26S proteasome (SPS2)

Summary for 6EPE

• Entry DOI: 10.2210/pdb6epe/pdb
• EMDB information: 3915
• Descriptor: Proteasome subunit alpha type-6, Proteasome subunit beta type-3, Proteasome subunit beta type-2, ... (32 entities in total)
• Functional Keywords: ups, substrate processing state, neuron degeneration, hydrolase
• Biological source: Rattus norvegicus (Rat); More
• Total number of polymer chains: 32
• Total formula weight: 1284003.13

Authors

Guo, Q.,Lehmer, C.,Martinez-Sanchez, A.,Rudack, T.,Beck, F.,Hartmann, H.,Hipp, M.S.,Hartl, F.U.,Edbauer, D.,Baumeister, W.,Fernandez-Busnadiego, R. (deposition date: 2017-10-11, release date: 2018-02-07, Last modification date: 2024-05-15)

Primary citation

Guo, Q.,Lehmer, C.,Martinez-Sanchez, A.,Rudack, T.,Beck, F.,Hartmann, H.,Perez-Berlanga, M.,Frottin, F.,Hipp, M.S.,Hartl, F.U.,Edbauer, D.,Baumeister, W.,Fernandez-Busnadiego, R.
In Situ Structure of Neuronal C9orf72 Poly-GA Aggregates Reveals Proteasome Recruitment.
Cell, 172:696-705.e12, 2018

PubMed Abstract: 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.

PubMed: 29398115
DOI: 10.1016/j.cell.2017.12.030

Experimental method

ELECTRON MICROSCOPY (12.8 Å)