دورية أكاديمية
A potent voltage-gated calcium channel inhibitor engineered from a nanobody targeted to auxiliary CaVβ subunits
| العنوان: | A potent voltage-gated calcium channel inhibitor engineered from a nanobody targeted to auxiliary CaVβ subunits |
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| المؤلفون: | Travis J Morgenstern, Jinseo Park, Qing R Fan, Henry M Colecraft |
| المصدر: | eLife, Vol 8 (2019) |
| بيانات النشر: | eLife Sciences Publications Ltd, 2019. |
| سنة النشر: | 2019 |
| المجموعة: | LCC:Medicine LCC:Science LCC:Biology (General) |
| مصطلحات موضوعية: | calcium channel, nanobody, ubiquitin, Nedd4, calcium channel beta, cavia porcellus, Medicine, Science, Biology (General), QH301-705.5 |
| الوصف: | Inhibiting high-voltage-activated calcium channels (HVACCs; CaV1/CaV2) is therapeutic for myriad cardiovascular and neurological diseases. For particular applications, genetically-encoded HVACC blockers may enable channel inhibition with greater tissue-specificity and versatility than is achievable with small molecules. Here, we engineered a genetically-encoded HVACC inhibitor by first isolating an immunized llama nanobody (nb.F3) that binds auxiliary HVACC CaVβ subunits. Nb.F3 by itself is functionally inert, providing a convenient vehicle to target active moieties to CaVβ-associated channels. Nb.F3 fused to the catalytic HECT domain of Nedd4L (CaV-aβlator), an E3 ubiquitin ligase, ablated currents from diverse HVACCs reconstituted in HEK293 cells, and from endogenous CaV1/CaV2 channels in mammalian cardiomyocytes, dorsal root ganglion neurons, and pancreatic β cells. In cardiomyocytes, CaV-aβlator redistributed CaV1.2 channels from dyads to Rab-7-positive late endosomes. This work introduces CaV-aβlator as a potent genetically-encoded HVACC inhibitor, and describes a general approach that can be broadly adapted to generate versatile modulators for macro-molecular membrane protein complexes. |
| نوع الوثيقة: | article |
| وصف الملف: | electronic resource |
| اللغة: | English |
| تدمد: | 2050-084X |
| Relation: | https://elifesciences.org/articles/49253; https://doaj.org/toc/2050-084X |
| DOI: | 10.7554/eLife.49253 |
| URL الوصول: | https://doaj.org/article/e56ce6dd3efa4e69a83ce9aa4dcbc733 |
| رقم الأكسشن: | edsdoj.56ce6dd3efa4e69a83ce9aa4dcbc733 |
| قاعدة البيانات: | Directory of Open Access Journals |
Full Text Finder | تدمد: | 2050084X |
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| DOI: | 10.7554/eLife.49253 |