The TAR binding dynamics and its implication in Tat degradation mechanism.
Biophys J
; 120(23): 5158-5168, 2021 12 07.
Article
en En
| MEDLINE
| ID: mdl-34762866
ABSTRACT
Human immunodeficiency virus (HIV) is a retrovirus that progressively attacks the human immune system. It is known that the HIV viral protein Tat recruits the host elongation factor, positive transcription elongation factor b (P-TEFb), onto the nascent HIV viral transactivation response element (TAR) RNA to overcome the elongation pause for active transcription of the entire viral genome. Interestingly, there exists an amplifying feedback loop between Tat and TAR-a reduction in Tat increases the elongation pause, resulting in more TAR RNA fragments instead of the entire viral genome transcript, and the TAR fragments as a scaffold for PRC2 complex in turn promote Tat ubiquitination and degradation. In this study, the structural ensembles and binding dynamics of various interfaces in the Tat/TAR/P-TEFb complex are probed by all-atom accelerated sampling molecular dynamics simulations. The results show that a protein-binding inhibitor F07#13 targeting the Tat/P-TEFb interface initiates the above feedback loop and shuts down the active transcription. Another RNA binding inhibitor, JB181, targeting the Tat/TAR interface, can prevent TAR from pulling down the Tat from P-TEFb protein and further reducing Tat degradation. The detailed mechanism of the complex dynamics helps elucidate how Tat and TAR coordinate the regulation between HIV genome transcription versus possible HIV latency.
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Duplicado del Terminal Largo de VIH
/
VIH-1
Límite:
Humans
Idioma:
En
Revista:
Biophys J
Año:
2021
Tipo del documento:
Article
País de afiliación:
China