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-Structure paper
タイトル | High resolution structures define divergent and convergent mechanisms of archaeal proteasome activation. |
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ジャーナル・号・ページ | Commun Biol, Vol. 6, Issue 1, Page 733, Year 2023 |
掲載日 | 2023年7月15日 |
著者 | Janelle J Y Chuah / Matthew S Rexroad / David M Smith / |
PubMed 要旨 | 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 ...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. |
リンク | Commun Biol / PubMed:37454196 / PubMed Central |
手法 | EM (単粒子) |
解像度 | 1.94 - 2.28 Å |
構造データ | EMDB-28876, PDB-8f66: EMDB-28878, PDB-8f6a: EMDB-28906, PDB-8f7k: |
化合物 | ChemComp-XIB: |
由来 |
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キーワード | HYDROLASE / Protease / threonine protease / endopeptidase activity |