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

Abstract

Human TIP30 is a cofactor that specifically enhances human immunodeficiency virus-1 (HIV-1) Tat-activated transcription [[1]Xiao H Tao Y Greenblatt J Roeder RG A cofactor, TIP30, specifically enhances HIV-1 Tat-activated transcription.Proc Natl Acad Sci USA. 1998; 95: 2146-2151Crossref Scopus (68) Google Scholar]. The sequence of human TIP30 is 98% identical to human CC3, a protein associated with the suppression of metastasis in small cell lung carcinomas [[2]Shtivelman E A link between metastasis and resistance to apoptosis of variant small cell lung carcinoma.Oncogene. 1997; 14: 2167-2173Crossref PubMed Scopus (104) Google Scholar]. 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 [[3]Altschul SF Madden TL Schäffer AA Zhang J Zhang Z Miller W Lipman DJ Gapped BLAST and PSI-BLAST: a new generation of protein database search programs.Nucleic Acids Res. 1997; 25: 3389-3402Crossref PubMed Scopus (57608) Google Scholar] of Aquifex aeolicus 2982870, which belongs to the short-chain dehydrogenase/reductase (SDR) family [[4]Baker ME Grundy WN Elkan CP A common ancestor for a subunit in the mitochondrial proton-translocating NADH:ubiquinone oxidoreductase (complex I) and short-chain dehydrogenases/reductases.Cell Mol Life Sci. 1999; 55: 450-455Crossref PubMed Scopus (11) Google Scholar], 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 [5Baker ME Blasco R Expansion 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.FEBS Lett. 1992; 301: 89-93Abstract Full Text PDF Scopus (104) Google Scholar, 6Jornvall H Persson B Krook M Atrian S Gonzalez-Duarte R Jeffrey J Ghosh D Short-chain dehydrogenases/reductases (SDR).Biochemistry. 1995; 34: 6003-6013Crossref PubMed Scopus (1133) Google Scholar]. Figure 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 [4Baker ME Grundy WN Elkan CP A common ancestor for a subunit in the mitochondrial proton-translocating NADH:ubiquinone oxidoreductase (complex I) and short-chain dehydrogenases/reductases.Cell Mol Life Sci. 1999; 55: 450-455Crossref PubMed Scopus (11) Google Scholar, 5Baker ME Blasco R Expansion 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.FEBS Lett. 1992; 301: 89-93Abstract Full Text PDF Scopus (104) Google Scholar, 6Jornvall H Persson B Krook M Atrian S Gonzalez-Duarte R Jeffrey J Ghosh D Short-chain dehydrogenases/reductases (SDR).Biochemistry. 1995; 34: 6003-6013Crossref PubMed Scopus (1133) Google Scholar, 7Tsigelny I Baker ME Structures important in mammalian 11β- and 17β-hydroxysteroid dehydrogenases.J Ster Biochem Molec Biol. 1995; 55: 589-600Crossref Scopus (21) Google Scholar, 8Thoden JB Frey PA Holden HM Crystal structures of the oxidized and reduced forms of UDP-galactose 4-epimerase isolated from Escherichia coli.Biochemistry. 1996; 35: 2557-2566Crossref Scopus (123) Google Scholar, 9Tanaka N Nonaka T Tanabe T Yoshimoto T Tsuru D Mitsui Y Crystal structures of the binary and ternary complexes of 7 alpha-hydroxysteroid dehydrogenase from Escherichia coli.Biochemistry. 1996; 35: 7715-7730Crossref Scopus (211) Google Scholar, 10Bailey TL Baker ME Elkan CP An artificial intelligence approach to motif discovery in protein sequences: application to steroid dehydrogenases.J Steroid Biochem Molec Biol. 1997; 52: 29-43Crossref Scopus (55) Google Scholar]. Residues in the carboxy-terminal third of TIP30 and CC3 correspond to the SDR substrate-binding site. Although most SDRs are oxidoreductases, spinach CSP41, which binds mRNA and has ribonuclease activity, was recently shown to belong to the SDR family [[11]Baker ME Grundy WN Elkan CP Spinach CSP41, an mRNA-binding protein and ribonuclease, is homologous to nucleotide-sugar epimerases and hydroxysteroid dehydrogenases.Biochem Biophys Res Commun. 1998; 248: 250-254Crossref PubMed Scopus (36) Google Scholar]. 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. ME Baker, Department of Medicine, 0823 University of California, San Diego, 9500 Gilman Drive, La Jolla, California 92093-0823, USA. e-mail: [email protected]