|
|
| Line 29: |
Line 29: |
|
| |
|
| == '''Mechanism''' == | | == '''Mechanism''' == |
| [[Image:Mechanism_figure.jpg |thumb|200 px|right| Recruitment of the components of a competent pre-initiation complex by acetylated Tat and cellular factors.]] | | [[Image:Kac_fig.gif |thumb|200 px|right| Acetylation and deacetylation of the lysine residue..]] |
| The human immunodeficiency virus type 1 (HIV-1) protein Tat is an atypical trans-activator of transcription which functions through binding to an RNA element known as the transactivation responsive region (TAR), located in the retroviral long-terminal repeat (LTR) [Cullen 1998], [Jeang et al. 1999] and [Karn 1999]. Tat binds to TAR RNA with high affinity but transiently [Keen et al. 1997] and [Rana and Jeang 1999]. Dissociation of Tat from TAR RNA facilitates Tat association with the assembled RNA polymerase II (RNAPII) complex [Deng et al. 2000] and [Kiernan et al. 1999]. The latter process enables the transcriptional machinery complex to elongate efficiently on the viral DNA template in order to produce full-length HIV transcripts during viral productive replication in infected cells [Adams et al. 1994] and [Garber and Jones 1999].The action of Tat has been well studied; however, the physiological mechanism through which Tat gains access to chromatin-associated LTRs is not understood.
| | Tat acetylation at K50 results in its dissociation from TAR RNA and promotes formation of a multiprotein complex composed of Tat, p300/CBP, and PCAF. [Benkirane et al. 1998]The bromodomains of PCAF and CBP have three major points of contact that allow for site-specific histone recognition. First, the acetylated lysine of the target protein enters a hydrophobic pocket embedded between the ZA and BC loops at the bottom of the protein. The Asn803 residue in the bromodomain forms a hydrogen bond with the amide nitrogen of the acetyl-lysine. Next, residues in the ZA and/or BC loops interact with residues adjacent to the acetyl-lysine, which reinforces the acetyl-lysine binding in the bromodomain. Finally, additional residues in the ZA and BC loops that face opposite to the bromodomain form hydrophobic and/ or electrostatic interaction with the target protein 3 residues away from the acetyl-lysine. This residue clamps on the BC loop together with the acetyl-lysine side chain that is bound inside the hydrophobic pocket of the bromodomain.[http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3339198/] |
| There is an increasing body of evidence to suggest that Tat activity requires its association with several multiprotein complexes, which include histone acetyltransferase (HAT), p300/CBP (CREB binding protein), and p300/CBP-associated factor (PCAF)<ref> http://www.sciencedirect.com/science/article/pii/S1097276502004835 </ref> Tat acetylation at K50 results in its dissociation from TAR RNA and promotes formation of a multiprotein complex comprised of Tat, p300/CBP, and PCAF [Benkirane et al. 1998]. Furthermore, it has been shown that the HAT activity of PCAF is preferentially required for Tat transactivation of transcription of the integrated HIV-1 LTRs (Benkirane et al., 1998).
| |
|
| |
|
| == '''Implications or Possible Applications''' == | | == '''Implications or Possible Applications''' == |
