Tat and Rev

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Tat is an unusual transcriptional activator that operates by binding to an RNA site (TAR) and enhancing elongation from the viral LTR. Tat and TAR form a larger complex with the cellular elongation factor P-TEFb, composed of cyclin T1 (CycT1) and Cdk9 subunits. Tat also interacts with other proteins of the transcriptional machinery. P-TEFb exists in two complexes in cells. In the small complex (SC), which consists of CycT1 and Cdk9, the kinase is active and phosphorylates the C-terminal domain (CTD) of RNA Pol II, leading to increased processivity. In the large comlex (LC), which consists of the HEXIM1 protein and 7SK snRNA in addition to P-TEFb, the kinase is inactive. Tat can displace HEXIM1 from 7SK snRNA and recruit the now active P-TEFb to the HIV LTR. To date, the NMR structures of only the Tat arginine-rich motif (ARM) peptide-TAR RNA and argininamide-TAR binary complexes have been solved. Studies of Tat in the HARC Center aim to determine the structures of Tat-P-TEFb-TAR complexes, as well as those of a minimal Tat-CycT1 chimera bound to TAR and of the LC. These structures will be compared to those of Tat- TAR complexes to ascertain similarities and differences in the binding surfaces and bound conformations and in order to better understand the postulated roles of induced fit in Tat function.