9BUZ

Thermoplasma acidophilum 20S proteasome - alphaV24Y

9BUZ の概要

• エントリーDOI: 10.2210/pdb9buz/pdb
• EMDBエントリー: 44914 44926
• 分子名称: Proteasome subunit alpha, Proteasome subunit beta (3 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: 686886.21

構造登録者

Chuah, J.,Smith, D. (登録日: 2024-05-18, 公開日: 2024-10-30, 最終更新日: 2025-04-16)

主引用文献

Chuah, J.J.Y.,Daugherty, M.R.,Smith, D.M.
Occupancy of the HbYX hydrophobic pocket is sufficient to induce gate opening in the archaeal 20S proteasomes.
Biorxiv, 2025

PubMed Abstract: Enhancing proteasome function has been a long-standing but challenging target of interest for the potential treatment of neurodegenerative diseases, emphasizing the importance of understanding proteasome activation mechanisms. Most proteasome activator complexes use the C-terminal HbYX (hydrophobic-tyrosine-almost any residue) motif to bind and trigger gate-opening in the 20S proteasome. This study defines a critical molecular interaction in the HbYX mechanism that triggers gate opening. We focus on the Hb site interaction and find it plays a surprisingly central and crucial role in driving the allosteric conformational changes that induce gate opening in the archaeal 20S. We examined the cryo-EM structure of two mutant archaeal proteasomes, αV24Y T20S and αV24F T20S. These two mutants were engineered to place a bulky aromatic residue in the HbYX hydrophobic pocket; both mutants are highly active, though their mechanisms of activation are undefined. Collectively, our findings indicate that the interaction between the Hb group of the HbYX motif and its corresponding hydrophobic pocket is sufficient to induce gate opening in a mechanistically similar way to the HbYX motif. The activation mechanism studied here involves the expansion of the hydrophobic binding site, allosterically altering the state of the IT switch thus triggering gate-opening. Furthermore, we show that the canonical αK66 residue, previously understood to be critical for proteasome activator binding, also plays a key role in stabilizing the open gate, irrespective of activator binding. This study differentiates between the residues in the HbYX motif that support binding interactions ("YX") versus those that allosterically contribute to gate opening ("Hb"). The insights reported here will guide future drug development efforts, particularly in designing small molecule proteasome activators, by targeting the identified hydrophobic pocket.

PubMed: 38826226
DOI: 10.1101/2024.05.21.595185

実験手法

ELECTRON MICROSCOPY (2.38 Å)