HIV-1 TAT is a natively unfolded protein: The solution conformation and dynamics of reduced HIV-1 TAT1-72 by NMR spectroscopy

doi:10.1074/jbc.M510748200

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Papers In Press, published online ahead of print January 19, 2006
J. Biol. Chem, 10.1074/jbc.M510748200
Submitted on October 3, 2005
Revised on January 11, 2006
Accepted on January 19, 2006

HIV-1 TAT is a natively unfolded protein: The solution conformation and dynamics of reduced HIV-1 TAT1-72 by NMR spectroscopy

Shaheen Shojania and Joe D. O'Neil

Chemistry Dept., University of Manitoba, Winnipeg, MB R3T 2N2

Corresponding Author: joneil{at}cc.umanitoba.ca

The Transactivator of transcription (Tat) is a small RNA-binding protein that plays a central role in the regulation of HIV-1 replication and in approaches to treating latently-infected cells. Its interactions with a wide variety of both intracellular and extracellular molecules is well documented. A molecular understanding of the multitude of Tat activities requires a determination of its structure and interactions with cellular and viral partners. To increase the dispersion of NMR signals and permit dynamics analysis by multinuclear NMR spectroscopy we have prepared uniformly 15N and 15N/13C-labelled Tat1-72 protein. The cysteine-rich protein is unambiguously reduced at pH 4.1 and NMR chemical shifts and coupling constants suggest that it exists in a random coil conformation. Line broadening and multiple peaks in the Cys-rich and core regions suggest that transient folding occurs in two of the five sequence domains. NMR relaxation parameters were measured and analysed by spectral density and Lipari-Szabo approaches both confirming the lack of structure throughout the length of the molecule. The absence of a fixed conformation and the observation of fast dynamics are consistent with the ability of Tat protein to interact with a wide variety of proteins and nucleic acid and supports the concept of a natively-unfolded protein.

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