High resolution structures define divergent and convergent mechanisms of archaeal proteasome activation
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-t...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2023-07-01
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| Series: | Communications Biology |
| Online Access: | https://doi.org/10.1038/s42003-023-05123-3 |
| _version_ | 1797778806668263424 |
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| author | Janelle J. Y. Chuah Matthew S. Rexroad David M. Smith |
| author_facet | Janelle J. Y. Chuah Matthew S. Rexroad David M. Smith |
| author_sort | Janelle J. Y. Chuah |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-12T23:21:53Z |
| format | Article |
| id | doaj.art-fe09edbf8aeb4680a7355cc00d5ba9d3 |
| institution | Directory Open Access Journal |
| issn | 2399-3642 |
| language | English |
| last_indexed | 2024-03-12T23:21:53Z |
| publishDate | 2023-07-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Communications Biology |
| spelling | doaj.art-fe09edbf8aeb4680a7355cc00d5ba9d32023-07-16T11:24:54ZengNature PortfolioCommunications Biology2399-36422023-07-016111610.1038/s42003-023-05123-3High resolution structures define divergent and convergent mechanisms of archaeal proteasome activationJanelle J. Y. Chuah0Matthew S. Rexroad1David M. Smith2Department of Biochemistry and Molecular Medicine, West Virginia University School of Medicine, 64 Medical Center Dr.Department of Biochemistry and Molecular Medicine, West Virginia University School of Medicine, 64 Medical Center Dr.Department of Biochemistry and Molecular Medicine, West Virginia University School of Medicine, 64 Medical Center Dr.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.https://doi.org/10.1038/s42003-023-05123-3 |
| spellingShingle | Janelle J. Y. Chuah Matthew S. Rexroad David M. Smith High resolution structures define divergent and convergent mechanisms of archaeal proteasome activation Communications Biology |
| title | High resolution structures define divergent and convergent mechanisms of archaeal proteasome activation |
| title_full | High resolution structures define divergent and convergent mechanisms of archaeal proteasome activation |
| title_fullStr | High resolution structures define divergent and convergent mechanisms of archaeal proteasome activation |
| title_full_unstemmed | High resolution structures define divergent and convergent mechanisms of archaeal proteasome activation |
| title_short | High resolution structures define divergent and convergent mechanisms of archaeal proteasome activation |
| title_sort | high resolution structures define divergent and convergent mechanisms of archaeal proteasome activation |
| url | https://doi.org/10.1038/s42003-023-05123-3 |
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