Abstract
Human TIP30 is a cofactor that specifically enhances human immunodeficiency virus-1 (HIV-1) Tat-activated transcription. The sequence of TIP30 is identical to that of CC3, a protein associated with metastasis suppression. TIP30/CC3 is a member of the short-chain dehydrogenases/reductases (SDR) family. Of the several experimentally determined SDR structures, Escherichia coli uridine diphosphate (UDP) galactose-4 epimerase is most similar to TIP30/CC3. Because the direct sequence similarity between TIP30/CC3 and E. coli UDP galactose-4 epimerase is low, we used the transitive nature of homology and employed two Aquifex aeolicus proteins as intermediaries in the homology modeling process. Comparison of our structural model with that of known SDRs reveals that TIP30/CC3 contains several well-conserved features, including a beta alpha beta fold at the amino terminus, which we predict binds NADP(H). TIP30/CC3 contains characteristic motifs at the catalytic site of SDRs, including a serine, tyrosine, and lysine that are important in catalyzing hydride transfer between substrate and cofactor. We also predict that a unique 20-amino acid sequence found at the amino terminus is an alpha-helix. Because this region contains several positively and negatively charged amino acids, it may dock TIP30/CC3 to other proteins. Our structural model points to this alpha-helix and the SDR-like part of TIP30/CC3 for mutagenesis experiments to elucidate its role in HIV-1 Tat-activated transcription, metastasis suppression, and other cellular functions.