Academic Journal
Rational engineering of an elevator-type metal transporter ZIP8 reveals a conditional selectivity filter critically involved in determining substrate specificity
| العنوان: | Rational engineering of an elevator-type metal transporter ZIP8 reveals a conditional selectivity filter critically involved in determining substrate specificity |
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| المؤلفون: | Jiang, Yuhan, Li, Zhen, Sui, Dexin, Sharma, Gaurav, Wang, Tianqi, MacRenaris, Keith, Takahashi, Hideki, Merz, Kenneth, Hu, Jian |
| المساهمون: | Foundation for the National Institutes of Health |
| المصدر: | Communications Biology ; volume 6, issue 1 ; ISSN 2399-3642 |
| بيانات النشر: | Springer Science and Business Media LLC |
| سنة النشر: | 2023 |
| الوصف: | Engineering of transporters to alter substrate specificity as desired holds great potential for applications, including metabolic engineering. However, the lack of knowledge on molecular mechanisms of substrate specificity hinders designing effective strategies for transporter engineering. Here, we applied an integrated approach to rationally alter the substrate preference of ZIP8, a Zrt-/Irt-like protein (ZIP) metal transporter with multiple natural substrates, and uncovered the determinants of substrate specificity. By systematically replacing the differentially conserved residues with the counterparts in the zinc transporter ZIP4, we created a zinc-preferring quadruple variant (Q180H/E343H/C310A/N357H), which exhibited largely reduced transport activities towards Cd 2+ , Fe 2+ , and Mn 2+ whereas increased activity toward Zn 2+ . Combined mutagenesis, modeling, covariance analysis, and computational studies revealed a conditional selectivity filter which functions only when the transporter adopts the outward-facing conformation. The demonstrated approach for transporter engineering and the gained knowledge about substrate specificity will facilitate engineering and mechanistic studies of other transporters. |
| نوع الوثيقة: | article in journal/newspaper |
| اللغة: | English |
| DOI: | 10.1038/s42003-023-05146-w |
| الاتاحة: | http://dx.doi.org/10.1038/s42003-023-05146-w https://www.nature.com/articles/s42003-023-05146-w.pdf https://www.nature.com/articles/s42003-023-05146-w |
| Rights: | https://creativecommons.org/licenses/by/4.0 ; https://creativecommons.org/licenses/by/4.0 |
| رقم الانضمام: | edsbas.1BB915B5 |
| قاعدة البيانات: | BASE |
| DOI: | 10.1038/s42003-023-05146-w |
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