Abstract
Retroviruses are eucaryotic viruses that carry their genetic information as an RNA rather than a DNA sequence. Based on their pathogenic potential, the family of retroviruses can be divided into three different subfamilies, that is the oncoviruses, the lentiviruses, and the spumaviruses. Oncoviruses, such as the Rous sarcoma virus (RSV) and the human T-cell leukemia viruses (HTLV), are cancer causing agents. Lentiviruses, or slow viruses, such as the equine infectious anemia virus (EIAV) and the human immunodeficiency virus (HIV) are non-neoplastic pathogens. Spumaviruses do not have any known pathogenic potential. All lentiviral genomes code for transactivator proteins (Tat) that positively regulate the expression of all viral genes. Tat protein action is absolutely essential for viral replication, and requires the binding to an RNA recognition sequence element (transactivation response element, TAR) located at the 5’ end of all viral transcripts. Tat proteins range in size between 75 and 130 amino acids (Jones & Peterlin, 1994). From sequence comparisons of lentiviral Tat proteins it was concluded that immunodeficiency virus Tat protein sequences are in general subdivided into five regions: an NH2-terminal region, a cysteine-rich region, a core region, a basic region, a glutamine-rich region, and a COOH-terminal region (table 1; (Dorn, 1990; Jones & Peterlin, 1994), and literature therein). The cysteine-rich region and a sequence homologous to the HIV-1 Tat COOH-terminus are not present in the EIAV Tat protein. The highly conserved core region encompasses amino acids Tyr35 through Tyr49 in EIAV Tat protein, and Tyr32 through Tyr47 in HIV-1 Tat protein.
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Discussion
Peter Wright - Paul, it is not about TFE. I am intrigued by your suggestions that there might be a helix-turn-helix motif in the Tat protein and I wonder whether you have done any sequence alignments. What is the known helix-turn-helix sequence because there are certain rules that apply there? Certain positions that have small sidechains for example do allow proper packing of the two helices. So it will be very interesting to see whether the sequences indicate the homologies. Even with the detailed ones, you are supposed to see these rules obeyed.
Paul Rösch - We tried to plot this alignment but we were unsuccessful. Maybe we did not try hard enough.
Wright - One has to look at how these helices are formed originally and see how it aligns with the canonical and non-canonical helix-turn-helix motif.
Rösch - It is a very important point. If we could find the helix-turn-helix. motif and the RNA binding motif, this would be good.
Julie Forman-Kay - Since Peter Wright did not ask you about TFE, I think I would like to, not to put you on the spot. I have a question. Did you see any difference in the dispersion of the chemical shifts in the aqueous solution from that in TFE and what mole % of TFE were you using?
Rösch - We were using 40% TFE. We did not see any strong alterations in the chemical shift.
Carol Post - Along those lines, have you tried any other kind of additive, or varying pH or ionic strength?
Rösch - We varied pH from 2.8 – 7.2, ionic strength from 0 – 300 mM salt. We tried a variety of conditions. The structure looked like a very flexible structure at the beginning, very unsatisfactory to us, so we tried all the secrets of the trade to induce secondary structure but we did not succeed by these methods, so we used TFE.
Thomas James - Paul, with your EIAV you have done some nitrogen labeling. How did your order parameter correlate with your structural domains that you found?
Rösch - Our calculation of order parameter was not very conclusive. We saw a huge difference between the relaxation times in the hydrophobic corner and the relaxation times in the so called “flexible domain”. But we did not come to the point that we calculated the order parameters because we had many problems with peak overlap especially in the flexible regions, so we didn’t dare to calculate numbers from that.
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Rösch, P. et al. (1996). The Structure of Lentiviral Tat Proteins in Solution. In: Rao, B.D.N., Kemple, M.D. (eds) NMR as a Structural Tool for Macromolecules. Springer, Boston, MA. https://doi.org/10.1007/978-1-4613-0387-9_22
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