Proteins typically use a nuclear localization signal (NLS) to localize to the nucleus. Tetracycline transactivator (TTA) needs to work in the nucleus, but I did not find an NLS in the structure.
Tetracycline transactivator is a fusion of tetracycline repressor of E. coli (P04483) and VP16 of HSV (although by blast I only found P04483).
The Tet-Off system makes use of the tetracycline transactivator (tTA) protein, which is created by fusing one protein, TetR (tetracycline repressor), found in Escherichia coli bacteria, with the activation domain of another protein, VP16, found in the herpes simplex virus.2. Source
There can be multiple NLS's, but the ones I checked I did not find here.
- TetR is a protein from E. coli, which has no nucleus, and the above sequence is a perfect match to P04483, so NLS is not expected here.
- VP16 is from HSV, and it is reported to use HCF-1 to locate to the nucleus.
VP16 itself does not possess a nuclear localization signal; it is transported to the nucleus by HCF-1 and then binds to Oct-1, which can also recognize the same target sequence. - Since only a domain of VP16 is (f)used in TTA, I am not sure if this is present.
- Vaysse 2013 explicitly added an SV40 NLS to TetR, although for a completely different reason (translocate the plasmid DNA in to the nucleus during transfection).
Sequence of Tetracycline transactivator (advanced)