Three-dimensional model of human TIP30, a coactivator for HIV-1 Tat-activated transcription, and CC3, a protein associated with metastasis suppression

Human TIP30 is a cofactor that specifically enhances human immunodeficiency virus-1 (HIV-1) Tat-activated transcription. The sequence of TIP30 is iden tical to that of CC3, a protein associated with metastasis suppression. TIP 30/CC3 is a member of the short-chain dehydrogenases/reductases (SDR) famil y. Of the several experimentally determined SDR structures, Escherichia col i uridine diphosphate (UDP) galactose-4 epimerase is most similar to TIP30/ CC3. Because the direct sequence similarity between TIP30/CC3 and E. coli U DP galactose-4 epimerase is low, we used the transitive nature of homology and employed two Aquifex aeolicus proteins as intermediaries In the homolog y modeling process. Comparison of our structural model with that of known S DRs reveals that TIP30/CC3 contains several well-conserved features, includ ing a beta alpha beta fold at the amino terminus, which we predict binds NA DP(H). TIP30/CC3 contains characteristic motifs at the catalytic site of SD Rs, including a serine, tyrosine, and lysine that are important in catalyzi ng hydride transfer between substrate and cofactor. We also predict that a unique 20-amino acid sequence found at the amino terminus is an cc-helix. B ecause this region contains several positively and negatively charged amino acids, it may dock TIP30/CC3 to other proteins. Our structural model point s to this cc-helix and the SDR-like part of TIP30/CC3 for mutagenesis exper iments to elucidate its role in HIV-1 Tat-activated transcription, metastas is suppression, and other cellular functions.