8F6A

Thermoplasma acidophilum 20S proteasome - wild type

8F6A の概要

• エントリーDOI: 10.2210/pdb8f6a/pdb
• EMDBエントリー: 28878
• 分子名称: Proteasome subunit beta, Proteasome subunit alpha (2 entities in total)
• 機能のキーワード: protease, threonine protease, endopeptidase activity, hydrolase
• 由来する生物種: Thermoplasma acidophilum; 詳細
• タンパク質・核酸の鎖数: 28
• 化学式量合計: 685989.61

構造登録者

Chuah, J.,Smith, D. (登録日: 2022-11-16, 公開日: 2023-08-30)

主引用文献

Chuah, J.J.Y.,Rexroad, M.S.,Smith, D.M.
High resolution structures define divergent and convergent mechanisms of archaeal proteasome activation.
Commun Biol, 6:733-733, 2023

PubMed Abstract: Considering the link between neurodegenerative diseases and impaired proteasome function, and the neuro-protective impact of enhanced proteasome activity in animal models, it's crucial to understand proteasome activation mechanisms. A hydrophobic-tyrosine-any residue (HbYX) motif on the C-termini of proteasome-activating complexes independently triggers gate-opening of the 20S core particle for protein degradation; however, the causal allosteric mechanism remains unclear. Our study employs a structurally irreducible dipeptide HbYX mimetic to investigate the allosteric mechanism of gate-opening in the archaeal proteasome. High-resolution cryo-EM structures pinpoint vital residues and conformational changes in the proteasome α-subunit implicated in HbYX-dependent activation. Using point mutations, we simulated the HbYX-bound state, providing support for our mechanistic model. We discerned four main mechanistic elements triggering gate-opening: 1) back-loop rearrangement adjacent to K66, 2) intra- and inter- α subunit conformational changes, 3) occupancy of the hydrophobic pocket, and 4) a highly conserved isoleucine-threonine pair in the 20S channel stabilizing the open and closed states, termed the "IT switch." Comparison of different complexes unveiled convergent and divergent mechanism of 20S gate-opening among HbYX-dependent and independent activators. This study delivers a detailed molecular model for HbYX-dependent 20S gate-opening, enabling the development of small molecule proteasome activators that hold promise to treat neurodegenerative diseases.

PubMed: 37454196
DOI: 10.1038/s42003-023-05123-3

実験手法

ELECTRON MICROSCOPY (2.06 Å)