Structural bioinformatic study of human mitochondrial respiratory integral membrane megacomplex and its AlphaFold3 predicted water-soluble QTY megacomplex analog
Human mitochondrial Complex I is one of the largest multi-subunit membrane protein megacomplexes, which plays a critical role in oxidative phosphorylation and ATP production. It is also involved in many neurodegenerative diseases. However, studying its structure and the mechanisms underlying proton...
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Cambridge University Press
2025-01-01
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| Series: | QRB Discovery |
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| Online Access: | https://www.cambridge.org/core/product/identifier/S263328922500002X/type/journal_article |
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| author | Edward Chen Shuguang Zhang |
| author_facet | Edward Chen Shuguang Zhang |
| author_sort | Edward Chen |
| collection | DOAJ |
| description | Human mitochondrial Complex I is one of the largest multi-subunit membrane protein megacomplexes, which plays a critical role in oxidative phosphorylation and ATP production. It is also involved in many neurodegenerative diseases. However, studying its structure and the mechanisms underlying proton translocation remains challenging due to the hydrophobic nature of its transmembrane parts. In this structural bioinformatic study, we used the QTY code to reduce the hydrophobicity of megacomplex I, while preserving its structure and function. We carried out the structural bioinformatics analysis of 20 key enzymes in the integral membrane parts. We compare their native structure, experimentally determined using Cryo-electron microscopy (CryoEM), with their water-soluble QTY analogs predicted using AlphaFold 3. Leveraging AlphaFold 3’s advanced capabilities in predicting protein–protein complex interactions, we further explore whether the QTY-code integral membrane proteins maintain their protein–protein interactions necessary to form the functional megacomplex. Our structural bioinformatics analysis not only demonstrates the feasibility of engineering water-soluble integral membrane proteins using the QTY code, but also highlights the potential to use the water-soluble membrane protein QTY analogs as soluble antigens for discovery of therapeutic monoclonal antibodies, thus offering promising implications for the treatment of various neurodegenerative diseases. |
| format | Article |
| id | doaj-art-059eac3e26de47ba9591b36e9e255b89 |
| institution | DOAJ |
| issn | 2633-2892 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Cambridge University Press |
| record_format | Article |
| series | QRB Discovery |
| spelling | doaj-art-059eac3e26de47ba9591b36e9e255b892025-08-20T02:52:30ZengCambridge University PressQRB Discovery2633-28922025-01-01610.1017/qrd.2025.2Structural bioinformatic study of human mitochondrial respiratory integral membrane megacomplex and its AlphaFold3 predicted water-soluble QTY megacomplex analogEdward Chen0https://orcid.org/0009-0002-1734-5702Shuguang Zhang1https://orcid.org/0000-0002-3856-3752Independent Researcher, Pittsburgh, PA, USAMedia Lab, Massachusetts Institute of Technology, Cambridge, MA, 02139, USAHuman mitochondrial Complex I is one of the largest multi-subunit membrane protein megacomplexes, which plays a critical role in oxidative phosphorylation and ATP production. It is also involved in many neurodegenerative diseases. However, studying its structure and the mechanisms underlying proton translocation remains challenging due to the hydrophobic nature of its transmembrane parts. In this structural bioinformatic study, we used the QTY code to reduce the hydrophobicity of megacomplex I, while preserving its structure and function. We carried out the structural bioinformatics analysis of 20 key enzymes in the integral membrane parts. We compare their native structure, experimentally determined using Cryo-electron microscopy (CryoEM), with their water-soluble QTY analogs predicted using AlphaFold 3. Leveraging AlphaFold 3’s advanced capabilities in predicting protein–protein complex interactions, we further explore whether the QTY-code integral membrane proteins maintain their protein–protein interactions necessary to form the functional megacomplex. Our structural bioinformatics analysis not only demonstrates the feasibility of engineering water-soluble integral membrane proteins using the QTY code, but also highlights the potential to use the water-soluble membrane protein QTY analogs as soluble antigens for discovery of therapeutic monoclonal antibodies, thus offering promising implications for the treatment of various neurodegenerative diseases.https://www.cambridge.org/core/product/identifier/S263328922500002X/type/journal_articleConvert hydrophobic alpha-helix to hydrophilic alpha-helix:Protein engineeringQTY codeWater-soluble transmembrane protein megacomplex |
| spellingShingle | Edward Chen Shuguang Zhang Structural bioinformatic study of human mitochondrial respiratory integral membrane megacomplex and its AlphaFold3 predicted water-soluble QTY megacomplex analog QRB Discovery Convert hydrophobic alpha-helix to hydrophilic alpha-helix:Protein engineering QTY code Water-soluble transmembrane protein megacomplex |
| title | Structural bioinformatic study of human mitochondrial respiratory integral membrane megacomplex and its AlphaFold3 predicted water-soluble QTY megacomplex analog |
| title_full | Structural bioinformatic study of human mitochondrial respiratory integral membrane megacomplex and its AlphaFold3 predicted water-soluble QTY megacomplex analog |
| title_fullStr | Structural bioinformatic study of human mitochondrial respiratory integral membrane megacomplex and its AlphaFold3 predicted water-soluble QTY megacomplex analog |
| title_full_unstemmed | Structural bioinformatic study of human mitochondrial respiratory integral membrane megacomplex and its AlphaFold3 predicted water-soluble QTY megacomplex analog |
| title_short | Structural bioinformatic study of human mitochondrial respiratory integral membrane megacomplex and its AlphaFold3 predicted water-soluble QTY megacomplex analog |
| title_sort | structural bioinformatic study of human mitochondrial respiratory integral membrane megacomplex and its alphafold3 predicted water soluble qty megacomplex analog |
| topic | Convert hydrophobic alpha-helix to hydrophilic alpha-helix:Protein engineering QTY code Water-soluble transmembrane protein megacomplex |
| url | https://www.cambridge.org/core/product/identifier/S263328922500002X/type/journal_article |
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