Intrinsic Disorder and Function of the HIV-1 Tat Protein

The type 1 Human Immunodeficiency Virus transcriptional regulator Tat is a small RNA-binding protein es- sential for viral gene expression and replication. The protein binds to a large number of proteins within infected cells and non-infected cells, and has been demonstrated to impact a wide variety of cellular activities. Early circular dichroism stud- ies showed a lack of regular secondary structure in the protein whereas proton NMR studies suggested several different conformations. Multinuclear NMR structure and dynamics analysis indicates that the reduced protein is intrinsically dis- ordered with a predominantly extended conformation at pH 4. Multiple resonances for several atoms suggest the existence of multiple local conformers in rapid equilibrium. An X-ray diffraction structure of equine Tat, in a complex with its cog- nate RNA and cyclin T1, supports this conclusion. Intrinsic disorder explains the protein's capacity to interact with multi- ple partners and effect multiple biological functions; the large buried surface in the X-ray diffraction structure illustrates how a disordered protein can have a high affinity and high specificity for its partners and how disordered Tat assembles a protein complex to enhance transcription elongation.