Role of Histidine 547 of Human Dopamine Transporter in Molecular Interaction with HIV-1 Tat and Dopamine Uptake
Year: 2016
Type: article
Abstract: HIV-1 Tat plays an important role in HIV-associated neurocognitive disorders (HAND) by disrupting neurotransmission including dopamine uptake by human dopamine transporter (hDAT). Previous studies have demonstrated that HIV-1 Tat directly binds to hDAT and some amino-acid mutations that attenuate the hDAT-Tat binding also significantly decreased dopamine uptake activity of hDAT. This combined computational-experimental study demonstrates that histidine-547 (H547) of hDAT plays a crucial role in the hDAT-Tat binding and dopamine uptake by hDAT, and that the H547A mutation can not only considerably attenuate Tat-induced inhibition of dopamine uptake, but also significantly increase the Vmax of hDAT for dopamine uptake. The finding of such an unusual hDAT mutant capable of both increasing the Vmax of hDAT for dopamine uptake and disrupting the hDAT-Tat binding may provide an exciting knowledge basis for development of novel concepts for therapeutic treatment of the HAND.
Source: Scientific Reports
DOI: 10.1038/srep27314
Institutions: University of Kentucky, University of South Carolina
Language: English
Subfield: Cellular and Molecular Neuroscience
Field: Neuroscience
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $2,690
Awards: G1363631510, G2111544953, G3275326173, G3408010684, G5401103934, Development of a Cocaine-Metabolizing Enzyme for Drug Overdose Treatment, Development of First-Pinciples Electronic Structure Approach for Studying Molecular Structures, Properties, and Reaction Mechanisms in Solution, High-activity mutants of cocaine esterase for treatment of drug addiction, Long-lasting cocaine-metabolizing enzyme for cocaine addiction treatment, G8253040971, Molecular mechanisms: Dysregulation of monoamine transporters by HIV-1Tat and cocaine, G951336646
OpenAlex ID: W2495473366