Three-dimensional model of human TIP30, a coactivator for HIV-1 Tat-activated transcription, and CC3, a protein associated with metastasis suppression
Three-dimensional model of human TIP30, a coactivator for HIV-1 Tat-activated transcription, and CC3, a protein associated with metastasis suppression
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DOI：
10.1007/s000180050047
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发表时间：
2000-05-01
影响因子：
8
通讯作者：
Pear, MR
中科院分区：
文献类型：
--
作者：
Baker, ME;Yan, L;Pear, MR
人类 TIP30 是一种辅助因子，可特异性增强人类免疫缺陷病毒 1 (HIV-1) Tat 激活的转录。 TIP30 的序列与 CC3 的序列相同，CC3 是一种与抑制转移相关的蛋白质。 TIP30/CC3 是短链脱氢酶/还原酶 (SDR) 家族的成员。在几个实验确定的 SDR 结构中，大肠杆菌尿苷二磷酸 (UDP) 半乳糖-4 差向异构酶与 TIP30/CC3 最相似。由于 TIP30/CC3 和大肠杆菌 UDP 半乳糖-4 差向异构酶之间的直接序列相似性较低，因此我们利用同源性的传递性质，并在同源建模过程中采用两个 Aquifex aeolicus 蛋白作为中介。我们的结构模型与已知 SDR 的比较表明，TIP30/CC3 包含几个保守的特征，包括氨基末端的 β α β 折叠，我们预测它会结合 NADP(H)。 TIP30/CC3 在 SDR 的催化位点包含特征基序，包括丝氨酸、酪氨酸和赖氨酸，它们对于催化底物和辅因子之间的氢化物转移非常重要。我们还预测在氨基末端发现的独特的 20 个氨基酸序列是 cc 螺旋。由于该区域包含多个带正电和负电的氨基酸，因此它可能会将 TIP30/CC3 与其他蛋白质对接。我们的结构模型指出这个 cc 螺旋和 TIP30/CC3 的 SDR 样部分用于诱变实验，以阐明其在 HIV-1 Tat 激活转录、转移抑制和其他细胞功能中的作用。
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 cc-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 cc-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.