Molecular Mechanism of HIV-1 Tat Interacting with Human Dopamine Transporter

Yaxia Yuan, Xiaoqin Huang, Narasimha M. Midde, Pamela M. Quizon, Wei Lun Sun, Jun Zhu, Chang Guo Zhan

Research output: Contribution to journalArticlepeer-review

37 Scopus citations

Abstract

Nearly 70% of HIV-1-infected individuals suffer from HIV-associated neurocognitive disorders (HAND). HIV-1 transactivator of transcription (Tat) protein is known to synergize with abused drugs and exacerbate the progression of central nervous system (CNS) pathology. Cumulative evidence suggest that the HIV-1 Tat protein exerts the neurotoxicity through interaction with human dopamine transporter (hDAT) in the CNS. Through computational modeling and molecular dynamics (MD) simulations, we develop a three-dimensional (3D) structural model for HIV-1 Tat binding with hDAT. The model provides novel mechanistic insights concerning how HIV-1 Tat interacts with hDAT and inhibits dopamine uptake by hDAT. In particular, according to the computational modeling, Tat binds most favorably with the outward-open state of hDAT. Residues Y88, K92, and Y470 of hDAT are predicted to be key residues involved in the interaction between hDAT and Tat. The roles of these hDAT residues in the interaction with Tat are validated by experimental tests through site-directed mutagensis and dopamine uptake assays. The agreement between the computational and experimental data suggests that the computationally predicted hDAT-Tat binding mode and mechanistic insights are reasonable and provide a new starting point to design further pharmacological studies on the molecular mechanism of HIV-1-associated neurocognitive disorders.

Original languageEnglish
Pages (from-to)658-665
Number of pages8
JournalACS Chemical Neuroscience
Volume6
Issue number4
DOIs
StatePublished - Apr 15 2015

Bibliographical note

Publisher Copyright:
© 2015 American Chemical Society.

Keywords

  • Transactivator of transcription
  • dopamine uptake
  • neurotoxicity
  • protein-protein interaction
  • viral protein

ASJC Scopus subject areas

  • Biochemistry
  • Physiology
  • Cognitive Neuroscience
  • Cell Biology

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