Mutational effects of human dopamine transporter at tyrosine88, lysine92, and histidine547 on basal and HIV-1 Tat-inhibited dopamine transport
| العنوان: | Mutational effects of human dopamine transporter at tyrosine88, lysine92, and histidine547 on basal and HIV-1 Tat-inhibited dopamine transport |
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| المؤلفون: | Wei-Lun Sun, Yaxia Yuan, Pamela M. Quizon, Jun Zhu, Matthew J. Strauss, Richard S. McCain, Chang-Guo Zhan |
| المصدر: | Scientific Reports, Vol 9, Iss 1, Pp 1-13 (2019) Scientific Reports |
| بيانات النشر: | Springer Science and Business Media LLC, 2019. |
| سنة النشر: | 2019 |
| مصطلحات موضوعية: | 0301 basic medicine, AIDS Dementia Complex, Dopamine, Mutant, lcsh:Medicine, Dopamine transport, HIV Infections, Article, 03 medical and health sciences, Basal (phylogenetics), 0302 clinical medicine, medicine, Humans, Point Mutation, Binding site, lcsh:Science, Dopamine transporter, Dopamine Plasma Membrane Transport Proteins, Multidisciplinary, biology, Chemistry, lcsh:R, Dopaminergic, Transporter, Cell biology, 030104 developmental biology, HIV-1, biology.protein, tat Gene Products, Human Immunodeficiency Virus, lcsh:Q, 030217 neurology & neurosurgery, medicine.drug |
| الوصف: | Dysregulation of dopaminergic system induced by HIV-1 Tat protein-mediated direct inhibition of the dopamine transporter (DAT) has been implicated as a mediating factor of HIV-1 associated neurocognitive disorders. We have reported that single point mutations on human DAT (hDAT) at tyrosine88 (Y88F), lysine92 (K92M), and histidine547 (H547A) differentially regulate basal dopamine uptake but diminish Tat-induced inhibition of dopamine uptake by changing dopamine transport process. This study evaluated the effects of double (Y88F/H547A) and triple (Y88F/K92M/H547A) mutations on basal dopamine uptake, Tat-induced inhibition of DAT function, and dynamic transport process. Compared to wild-type hDAT, the Vmax values of [3H]Dopamine uptake were increased by 96% in Y88F/H547A but decreased by 97% in Y88F/K92M/H547A. [3H]WIN35,428 binding sites were not altered in Y88F/H547A but decreased in Y88F/K92M/H547A. Y88F/H547A mutant attenuated Tat-induced inhibition of dopamine uptake observed in wild-type hDAT. Y88F/H547A displayed an attenuation of zinc-augmented [3H]WIN35,428 binding, increased basal dopamine efflux, and reduced amphetamine-induced dopamine efflux, indicating this mutant alters transporter conformational transitions. These findings further demonstrate that both tyrosine88 and histidine547 on hDAT play a key role in stabilizing basal dopamine transport and Tat-DAT integration. This study provides mechanistic insights into developing small molecules to block multiple sites in DAT for Tat binding. |
| تدمد: | 2045-2322 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::780e4367aeddbd0128f31bb2a802cefe https://doi.org/10.1038/s41598-019-39872-1 |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi.dedup.....780e4367aeddbd0128f31bb2a802cefe |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 20452322 |
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