Engineering of photo-inducible binary interaction tools for biomedical applications
Abstract The ssrA-sspB dimerization system, derived from the bacterial degradation machinery, comprises a 7-residue ssrA peptide and its binding partner sspB. The compact size of ssrA makes it ideal for insertion into proteins of interest to manipulate host protein function by engineered light-respo...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2025-07-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-61710-4 |
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| author | Yi-Tsang Lee Lei Guo Tien-Hung Lan Tatsuki Nonomura Gan Liu Guolin Ma Rui Wang Yun Huang Yubin Zhou |
| author_facet | Yi-Tsang Lee Lei Guo Tien-Hung Lan Tatsuki Nonomura Gan Liu Guolin Ma Rui Wang Yun Huang Yubin Zhou |
| author_sort | Yi-Tsang Lee |
| collection | DOAJ |
| description | Abstract The ssrA-sspB dimerization system, derived from the bacterial degradation machinery, comprises a 7-residue ssrA peptide and its binding partner sspB. The compact size of ssrA makes it ideal for insertion into proteins of interest to manipulate host protein function by engineered light-responsive sspB. In contrast to the LOV2 caging strategy employed to develop optical dimerizers, we present herein two distinct photo-inducible binary interaction tools (PhoBITs) systems: PhoBIT1, a light-OFF switch generated by integrating LOV2 into sspB, and PhoBIT2, a light-ON switch building upon an evolved ssrA/CRY2-sspB pair with minimal basal interaction. These tools enable mechanistic dissection and optogenetic modulation of GPCRs, ion channels, necroptosis, and innate immune signaling. When incorporated into a monobody, PhoBIT2 allows photo-switchable inhibition of an oncogenic fusion protein to curtail leukemogenesis in vivo. Collectively, through targeted ssrA insertions, PhoBITs offer versatile control over diverse protein functions, thereby expanding possibilities for optogenetic engineering and potential therapeutic applications. |
| format | Article |
| id | doaj-art-47eaa1874e224e8e8b5cc32740395765 |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-47eaa1874e224e8e8b5cc327403957652025-08-20T03:43:14ZengNature PortfolioNature Communications2041-17232025-07-0116111810.1038/s41467-025-61710-4Engineering of photo-inducible binary interaction tools for biomedical applicationsYi-Tsang Lee0Lei Guo1Tien-Hung Lan2Tatsuki Nonomura3Gan Liu4Guolin Ma5Rui Wang6Yun Huang7Yubin Zhou8Center for Translational Cancer Research, Institute of Biosciences and Technology, Texas A&M UniversityCenter for Epigenetics and Disease Prevention, Institute of Biosciences and Technology, Texas A&M UniversityCenter for Translational Cancer Research, Institute of Biosciences and Technology, Texas A&M UniversityCenter for Translational Cancer Research, Institute of Biosciences and Technology, Texas A&M UniversityCenter for Translational Cancer Research, Institute of Biosciences and Technology, Texas A&M UniversityCenter for Translational Cancer Research, Institute of Biosciences and Technology, Texas A&M UniversityCenter for Translational Cancer Research, Institute of Biosciences and Technology, Texas A&M UniversityCenter for Epigenetics and Disease Prevention, Institute of Biosciences and Technology, Texas A&M UniversityCenter for Translational Cancer Research, Institute of Biosciences and Technology, Texas A&M UniversityAbstract The ssrA-sspB dimerization system, derived from the bacterial degradation machinery, comprises a 7-residue ssrA peptide and its binding partner sspB. The compact size of ssrA makes it ideal for insertion into proteins of interest to manipulate host protein function by engineered light-responsive sspB. In contrast to the LOV2 caging strategy employed to develop optical dimerizers, we present herein two distinct photo-inducible binary interaction tools (PhoBITs) systems: PhoBIT1, a light-OFF switch generated by integrating LOV2 into sspB, and PhoBIT2, a light-ON switch building upon an evolved ssrA/CRY2-sspB pair with minimal basal interaction. These tools enable mechanistic dissection and optogenetic modulation of GPCRs, ion channels, necroptosis, and innate immune signaling. When incorporated into a monobody, PhoBIT2 allows photo-switchable inhibition of an oncogenic fusion protein to curtail leukemogenesis in vivo. Collectively, through targeted ssrA insertions, PhoBITs offer versatile control over diverse protein functions, thereby expanding possibilities for optogenetic engineering and potential therapeutic applications.https://doi.org/10.1038/s41467-025-61710-4 |
| spellingShingle | Yi-Tsang Lee Lei Guo Tien-Hung Lan Tatsuki Nonomura Gan Liu Guolin Ma Rui Wang Yun Huang Yubin Zhou Engineering of photo-inducible binary interaction tools for biomedical applications Nature Communications |
| title | Engineering of photo-inducible binary interaction tools for biomedical applications |
| title_full | Engineering of photo-inducible binary interaction tools for biomedical applications |
| title_fullStr | Engineering of photo-inducible binary interaction tools for biomedical applications |
| title_full_unstemmed | Engineering of photo-inducible binary interaction tools for biomedical applications |
| title_short | Engineering of photo-inducible binary interaction tools for biomedical applications |
| title_sort | engineering of photo inducible binary interaction tools for biomedical applications |
| url | https://doi.org/10.1038/s41467-025-61710-4 |
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