TIP30, a cofactor for HIV-1 Tat-activated transcription, is homologous to short-chain dehydrogenases/reductases.

Human TIP30 is a cofactor that specifically enhances human immunodeficiency virus-1 (HIV-1) Tat-activated transcription [1xA cofactor, TIP30, specifically enhances HIV-1 Tat-activated transcription. Xiao, H, Tao, Y, Greenblatt, J, and Roeder, RG. Proc Natl Acad Sci USA. 1998; 95: 2146–2151Crossref | Scopus (62)See all References[1]. The sequence of human TIP30 is 98% identical to human CC3, a protein associated with the suppression of metastasis in small cell lung carcinomas [2xA link between metastasis and resistance to apoptosis of variant small cell lung carcinoma. Shtivelman, E. Oncogene. 1997; 14: 2167–2173Crossref | PubMedSee all References[2]. CC3 is also expressed in a variety of cells, including heart, brain, lung, kidney, skeletal muscle and pancreas, in which its function is unknown. A pairwise gapped comparison [3xGapped BLAST and PSI-BLAST: a new generation of protein database search programs. Altschul, SF, Madden, TL, Schaffer, AA, Zhang, J, Zhang, Z, Miller, W, and Lipman, DJ. Nucleic Acids Res. 1997; 25: 3389–3402Crossref | PubMed | Scopus (45164)See all References[3] of Aquifex aeolicus 2982870, which belongs to the short-chain dehydrogenase/reductase (SDR) family [4xA common ancestor for a subunit in the mitochondrial proton-translocating NADH:ubiquinone oxidoreductase (complex I) and short-chain dehydrogenases/reductases. Baker, ME, Grundy, WN, and Elkan, CP. Cell Mol Life Sci. 1999; 55: 450–455Crossref | Scopus (10)See all References[4], with TIP30 yielded an E-value of 3 × 10−4, indicating that TIP30 also belongs to the SDR family. Because of the unusual nature of this discovery, we also investigated the ancestry of human TIP30 with the database-searching program, using as cutoff an E-value of 10−5 for including a protein in the position-dependent scoring matrix. (The default cutoff was an E-value of 10−3.) Thus, A. aeolicus 2982870 was not included in the first iteration. Nevertheless, the first iteration yielded an E-value of 10−10 for A. aeolicus 2982870. Moreover, the third iteration yielded an E-value of 7 × 10−21 for Escherichia coli UDP-galactose-4-epimerase, a known SDR [[5]xExpansion of the mammalian 3β-hydroxysteroid dehydrogenase/plant dihydroflavonol reductase superfamily to include a bacterial cholesterol dehydrogenase, a bacterial UDP-galactose-4-epimerase, and open reading frames in vaccinia virus and fish lymphocystis disease virus. Baker, ME and Blasco, R. FEBS Lett. 1992; 301: 89–93Abstract | Full Text PDF | Scopus (92)See all References, [6]xShort-chain dehydrogenases/reductases (SDR). Jornvall, H, Persson, B, Krook, M, Atrian, S, Gonzalez-Duarte, R, Jeffrey, J, and Ghosh, D. Biochemistry. 1995; 34: 6003–6013Crossref | PubMedSee all References].Figure 1Figure 1 shows a sequence alignment of TIP30, A. aeolicus 2982870 and E. coli UDP-galactose-4- epimerase. The amino terminus of TIP30 has the Gly-Xaa-Xaa-Gly-Xaa- Xaa-Gly motif (in which Xaa represents any amino acid) found in the nucleotide cofactor binding domain. Furthermore, Ser132, Tyr143 and Lys147 align with the known active residues in the catalytic site of SDRs [[4]xA common ancestor for a subunit in the mitochondrial proton-translocating NADH:ubiquinone oxidoreductase (complex I) and short-chain dehydrogenases/reductases. Baker, ME, Grundy, WN, and Elkan, CP. Cell Mol Life Sci. 1999; 55: 450–455Crossref | Scopus (10)See all References, [5]xExpansion of the mammalian 3β-hydroxysteroid dehydrogenase/plant dihydroflavonol reductase superfamily to include a bacterial cholesterol dehydrogenase, a bacterial UDP-galactose-4-epimerase, and open reading frames in vaccinia virus and fish lymphocystis disease virus. Baker, ME and Blasco, R. FEBS Lett. 1992; 301: 89–93Abstract | Full Text PDF | Scopus (92)See all References, [6]xShort-chain dehydrogenases/reductases (SDR). Jornvall, H, Persson, B, Krook, M, Atrian, S, Gonzalez-Duarte, R, Jeffrey, J, and Ghosh, D. Biochemistry. 1995; 34: 6003–6013Crossref | PubMedSee all References, [7]xStructures important in mammalian 11β- and 17β-hydroxysteroid dehydrogenases. Tsigelny, I and Baker, ME. J Ster Biochem Molec Biol. 1995; 55: 589–600Crossref | Scopus (20)See all References, [8]xCrystal structures of the oxidized and reduced forms of UDP-galactose 4-epimerase isolated from Escherichia coli. Thoden, JB, Frey, PA, and Holden, HM. Biochemistry. 1996; 35: 2557–2566Crossref | Scopus (113)See all References, [9]xCrystal structures of the binary and ternary complexes of 7 alpha-hydroxysteroid dehydrogenase from Escherichia coli. Tanaka, N, Nonaka, T, Tanabe, T, Yoshimoto, T, Tsuru, D, and Mitsui, Y. Biochemistry. 1996; 35: 7715–7730CrossrefSee all References, [10]xAn artificial intelligence approach to motif discovery in protein sequences: application to steroid dehydrogenases. Bailey, TL, Baker, ME, and Elkan, CP. J Steroid Biochem Molec Biol. 1997; 52: 29–43Crossref | Scopus (48)See all References]. Residues in the carboxy-terminal third of TIP30 and CC3 correspond to the SDR substrate-binding site.Figure 1Sequence alignment of human TIP30 with A. aeolicus 2982870 and E. coli UDP-galactose 4-epimerase. Glycine residues in the nucleotide-binding domain are shown in bold; the catalytically important serine (S), tyrosine (Y) and lysine (K) residues are underlined and marked with an asterisk.View Large Image | View Hi-Res Image | Download PowerPoint SlideAlthough most SDRs are oxidoreductases, spinach CSP41, which binds mRNA and has ribonuclease activity, was recently shown to belong to the SDR family [11xSpinach CSP41, an mRNA-binding protein and ribonuclease, is homologous to nucleotide-sugar epimerases and hydroxysteroid dehydrogenases. Baker, ME, Grundy, WN, and Elkan, CP. Biochem Biophys Res Commun. 1998; 248: 250–254Crossref | Scopus (30)See all References[11]. Whatever TIP30's enzyme activity is, it may be important in enhancing transcription of HIV-1 Tat, in which case, inhibitors of TIP30 would be useful for controlling replication of HIV-1. Similarly, elucidation of the enzymatic activity of CC3 could lead to strategies for controlling metastasis of small cell lung carcinomas, as well as elucidating CC3's function in normal cells.