AFF4 binding to Tat-P-TEFb indirectly stimulates TAR recognition of super elongation complexes at the HIV promoter

摘要

The rate at which many genes are expressed as proteins depends on a process called transcriptional elongation. This process takes place as the region of DNA that defines the gene is transcribed into an RNA molecule, and it is catalyzed by an enzyme called RNA polymerase II. However, this process often stalls shortly after it starts, and another enzyme called a positive transcription elongation factor is needed to restart it. The human immunodeficiency virus (HIV) is a retrovirus that hijacks the gene expression machinery inside immune cells in order to replicate itself. To do this as efficiently as possible, the elongation factor needs to restart the transcription process as quickly as possible. To ensure that this happens the virus produces a protein called Tat that binds to the short region of RNA that has already been made. At the same time the Tat protein also combines with other proteins to form a multi-protein machine called the super elongation complex. Other proteins in the super elongation complex include a ‘scaffold’ protein called AFF4, a positive elongation factor called P-TEFb, and at least two additional transcription factors. Until recently researchers did not know how the Tat protein was able to recruit super elongation complexes to the correct location without recruiting other complexes that contained similar protein subunits. Now Schulze-Gahmen et al. have shed new light on this mystery by working out the crystal structure of the complex formed by the elongation factor P-TEFb when it forms a complex with the Tat protein and a scaffold protein called AFF4. The results show that direct interactions between the Tat and scaffold proteins help to recruit the super elongation complex to the correct location. The three-way interactions between Tat, AFF4, and P-TEFb form a binding surface that encourages the complex to bind to the RNA. Overall, Schulze-Gahmen et al. show that the super elongation complex is much more likely to be recognized by the Tat protein and then bind to RNA than just the elongation factor on its own.