Flavivirus NS4B proteins do not form homodimers: discrepancies with an AlphaFold-based oligomeric model
In flaviviruses such as Dengue, Zika or West Nile virus (DENV, ZIKV or WNV), non-structural protein 4B (NS4B) participates in membrane remodeling during infection and is critical for virulence and host immunity. Despite the important roles and confirmed drug target status for NS4B, no detailed struc...
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Elsevier
2025-01-01
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| Series: | Computational and Structural Biotechnology Journal |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2001037025001497 |
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| author | Wahyu Surya Paula Tan Shwe Sin Honey Devanshu Mehta Jaume Torres |
| author_facet | Wahyu Surya Paula Tan Shwe Sin Honey Devanshu Mehta Jaume Torres |
| author_sort | Wahyu Surya |
| collection | DOAJ |
| description | In flaviviruses such as Dengue, Zika or West Nile virus (DENV, ZIKV or WNV), non-structural protein 4B (NS4B) participates in membrane remodeling during infection and is critical for virulence and host immunity. Despite the important roles and confirmed drug target status for NS4B, no detailed structure is available. Flavivirus NS4B proteins have five hydrophobic domains and have been proposed to form homodimers. Herein, we have used AlphaFold to explore its multimeric organization in a diverse set of five sequences of flaviviruses. AlphaFold correctly predicts the α-helical segments identified by solution NMR, but with a fold that differs from current models involving regular transmembrane helices. Oligomers of increasing size were evaluated using a combined AlphaFold score, with optimal value centered around decamers (n = 10). We tested this model experimentally using ZIKV NS4B protein. Biochemical and biophysical data produced an oligomer larger than the current dimeric model, at least pentameric, and possibly hexameric. Overall, our results suggest a ‘regular’ NS4B oligomer in ZIKV that is at least pentameric with five regular transmembrane helices. Although no evidence was found for the ‘irregular’ Alphafold-predicted model, it is intriguing that it is common to all sequences tested. Interference with the formation of an NS4B oligomer may be a general novel approach to treat flavivirus infection. |
| format | Article |
| id | doaj-art-410f5fa2107a4d44a2569c6bcf3ea9b0 |
| institution | DOAJ |
| issn | 2001-0370 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Computational and Structural Biotechnology Journal |
| spelling | doaj-art-410f5fa2107a4d44a2569c6bcf3ea9b02025-08-20T03:13:59ZengElsevierComputational and Structural Biotechnology Journal2001-03702025-01-01271660167210.1016/j.csbj.2025.04.026Flavivirus NS4B proteins do not form homodimers: discrepancies with an AlphaFold-based oligomeric modelWahyu Surya0Paula Tan1Shwe Sin Honey2Devanshu Mehta3Jaume Torres4School of Biological Sciences, Nanyang Technological University, 60 Nanyang Drive, Singapore 637551, SingaporeSchool of Biological Sciences, Nanyang Technological University, 60 Nanyang Drive, Singapore 637551, SingaporeSchool of Biological Sciences, Nanyang Technological University, 60 Nanyang Drive, Singapore 637551, SingaporeSchool of Biological Sciences, Nanyang Technological University, 60 Nanyang Drive, Singapore 637551, SingaporeCorresponding author.; School of Biological Sciences, Nanyang Technological University, 60 Nanyang Drive, Singapore 637551, SingaporeIn flaviviruses such as Dengue, Zika or West Nile virus (DENV, ZIKV or WNV), non-structural protein 4B (NS4B) participates in membrane remodeling during infection and is critical for virulence and host immunity. Despite the important roles and confirmed drug target status for NS4B, no detailed structure is available. Flavivirus NS4B proteins have five hydrophobic domains and have been proposed to form homodimers. Herein, we have used AlphaFold to explore its multimeric organization in a diverse set of five sequences of flaviviruses. AlphaFold correctly predicts the α-helical segments identified by solution NMR, but with a fold that differs from current models involving regular transmembrane helices. Oligomers of increasing size were evaluated using a combined AlphaFold score, with optimal value centered around decamers (n = 10). We tested this model experimentally using ZIKV NS4B protein. Biochemical and biophysical data produced an oligomer larger than the current dimeric model, at least pentameric, and possibly hexameric. Overall, our results suggest a ‘regular’ NS4B oligomer in ZIKV that is at least pentameric with five regular transmembrane helices. Although no evidence was found for the ‘irregular’ Alphafold-predicted model, it is intriguing that it is common to all sequences tested. Interference with the formation of an NS4B oligomer may be a general novel approach to treat flavivirus infection.http://www.sciencedirect.com/science/article/pii/S2001037025001497FlavivirusDengueZikaNon-structural protein 4BOligomerizationAlphaFold |
| spellingShingle | Wahyu Surya Paula Tan Shwe Sin Honey Devanshu Mehta Jaume Torres Flavivirus NS4B proteins do not form homodimers: discrepancies with an AlphaFold-based oligomeric model Computational and Structural Biotechnology Journal Flavivirus Dengue Zika Non-structural protein 4B Oligomerization AlphaFold |
| title | Flavivirus NS4B proteins do not form homodimers: discrepancies with an AlphaFold-based oligomeric model |
| title_full | Flavivirus NS4B proteins do not form homodimers: discrepancies with an AlphaFold-based oligomeric model |
| title_fullStr | Flavivirus NS4B proteins do not form homodimers: discrepancies with an AlphaFold-based oligomeric model |
| title_full_unstemmed | Flavivirus NS4B proteins do not form homodimers: discrepancies with an AlphaFold-based oligomeric model |
| title_short | Flavivirus NS4B proteins do not form homodimers: discrepancies with an AlphaFold-based oligomeric model |
| title_sort | flavivirus ns4b proteins do not form homodimers discrepancies with an alphafold based oligomeric model |
| topic | Flavivirus Dengue Zika Non-structural protein 4B Oligomerization AlphaFold |
| url | http://www.sciencedirect.com/science/article/pii/S2001037025001497 |
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