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Structural Insights into the Binding and Degradation Mechanisms of Protoporphyrin IX by the Translocator Protein TSPO
[Image: see text] The 18 kDa translocator protein (TSPO) has gained considerable attention as a clinical biomarker for neuroinflammation and a potential therapeutic target. However, the mechanisms by which TSPO associates with ligands, particularly the endogenous porphyrin ligand protoporphyrin IX (...
Autores principales: | , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Chemical Society
2023
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10598825/ https://www.ncbi.nlm.nih.gov/pubmed/37885593 http://dx.doi.org/10.1021/jacsau.3c00514 |
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author | Yeh, Pei-Shan Li, Chieh-Chin Lu, Yi-Shan Chiang, Yun-Wei |
author_facet | Yeh, Pei-Shan Li, Chieh-Chin Lu, Yi-Shan Chiang, Yun-Wei |
author_sort | Yeh, Pei-Shan |
collection | PubMed |
description | [Image: see text] The 18 kDa translocator protein (TSPO) has gained considerable attention as a clinical biomarker for neuroinflammation and a potential therapeutic target. However, the mechanisms by which TSPO associates with ligands, particularly the endogenous porphyrin ligand protoporphyrin IX (PpIX), remain poorly understood. In this study, we employed mutagenesis- and spectroscopy-based functional assays to investigate TSPO-mediated photo-oxidative degradation of PpIX and identify key residues involved in the reaction. We provide structural evidence using electron spin resonance, which sheds light on the highly conserved intracellular loop (LP1) connecting transmembrane 1 (TM1) and TM2. Our findings show that LP1 does not act as a lid to regulate ligand binding; instead, it interacts strongly with the TM3–TM4 linker (LP3) to stabilize the local structure of LP3. This LP1–LP3 interaction is crucial for maintaining the binding pocket structure, which is essential for proper ligand binding. Our results also demonstrate that PpIX accesses the pocket through the lipid bilayer without requiring conformational changes in TSPO. This study provides an improved understanding of TSPO-mediated PpIX degradation, highlighting potential therapeutic strategies to regulate the reaction. |
format | Online Article Text |
id | pubmed-10598825 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | American Chemical Society |
record_format | MEDLINE/PubMed |
spelling | pubmed-105988252023-10-26 Structural Insights into the Binding and Degradation Mechanisms of Protoporphyrin IX by the Translocator Protein TSPO Yeh, Pei-Shan Li, Chieh-Chin Lu, Yi-Shan Chiang, Yun-Wei JACS Au [Image: see text] The 18 kDa translocator protein (TSPO) has gained considerable attention as a clinical biomarker for neuroinflammation and a potential therapeutic target. However, the mechanisms by which TSPO associates with ligands, particularly the endogenous porphyrin ligand protoporphyrin IX (PpIX), remain poorly understood. In this study, we employed mutagenesis- and spectroscopy-based functional assays to investigate TSPO-mediated photo-oxidative degradation of PpIX and identify key residues involved in the reaction. We provide structural evidence using electron spin resonance, which sheds light on the highly conserved intracellular loop (LP1) connecting transmembrane 1 (TM1) and TM2. Our findings show that LP1 does not act as a lid to regulate ligand binding; instead, it interacts strongly with the TM3–TM4 linker (LP3) to stabilize the local structure of LP3. This LP1–LP3 interaction is crucial for maintaining the binding pocket structure, which is essential for proper ligand binding. Our results also demonstrate that PpIX accesses the pocket through the lipid bilayer without requiring conformational changes in TSPO. This study provides an improved understanding of TSPO-mediated PpIX degradation, highlighting potential therapeutic strategies to regulate the reaction. American Chemical Society 2023-10-06 /pmc/articles/PMC10598825/ /pubmed/37885593 http://dx.doi.org/10.1021/jacsau.3c00514 Text en © 2023 The Authors. Published by American Chemical Society https://creativecommons.org/licenses/by-nc-nd/4.0/Permits non-commercial access and re-use, provided that author attribution and integrity are maintained; but does not permit creation of adaptations or other derivative works (https://creativecommons.org/licenses/by-nc-nd/4.0/). |
spellingShingle | Yeh, Pei-Shan Li, Chieh-Chin Lu, Yi-Shan Chiang, Yun-Wei Structural Insights into the Binding and Degradation Mechanisms of Protoporphyrin IX by the Translocator Protein TSPO |
title | Structural Insights
into the Binding and Degradation
Mechanisms of Protoporphyrin IX by the Translocator Protein TSPO |
title_full | Structural Insights
into the Binding and Degradation
Mechanisms of Protoporphyrin IX by the Translocator Protein TSPO |
title_fullStr | Structural Insights
into the Binding and Degradation
Mechanisms of Protoporphyrin IX by the Translocator Protein TSPO |
title_full_unstemmed | Structural Insights
into the Binding and Degradation
Mechanisms of Protoporphyrin IX by the Translocator Protein TSPO |
title_short | Structural Insights
into the Binding and Degradation
Mechanisms of Protoporphyrin IX by the Translocator Protein TSPO |
title_sort | structural insights
into the binding and degradation
mechanisms of protoporphyrin ix by the translocator protein tspo |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10598825/ https://www.ncbi.nlm.nih.gov/pubmed/37885593 http://dx.doi.org/10.1021/jacsau.3c00514 |
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