Abstract
The type 1 Human Immunodeficiency Virus transcriptional regulator Tat is a small RNA-binding protein essential 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 studies 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 disordered 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 cognate RNA and cyclin T1, supports this conclusion. Intrinsic disorder explains the proteins capacity to interact with multiple 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.
Keywords: Circular dichroism, HIV-1, intrinsically disordered proteins, NMR spectroscopy, Tat, X-ray diffraction
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