Institute of Structural Biology, Helmholtz Zentrum München, Neuherberg 85 764, Germany.
Center for Integrated Protein Science Munich, Department Chemie, TU München, Garching 85748, Germany.
Nucleic Acids Res. 2019 May 21;47(9):4859-4871. doi: 10.1093/nar/gkz185.
The HIV-1 protein Rev is essential for virus replication and ensures the expression of partially spliced and unspliced transcripts. We identified a ULM (UHM ligand motif) motif in the Arginine-Rich Motif (ARM) of the Rev protein. ULMs (UHM ligand motif) mediate protein interactions during spliceosome assembly by binding to UHM (U2AF homology motifs) domains. Using NMR, biophysical methods and crystallography we show that the Rev ULM binds to the UHMs of U2AF65 and SPF45. The highly conserved Trp45 in the Rev ULM is crucial for UHM binding in vitro, for Rev co-precipitation with U2AF65 in human cells and for proper processing of HIV transcripts. Thus, Rev-ULM interactions with UHM splicing factors contribute to the regulation of HIV-1 transcript processing, also at the splicing level. The Rev ULM is an example of viral mimicry of host short linear motifs that enables the virus to interfere with the host molecular machinery.
HIV-1 蛋白 Rev 对于病毒复制至关重要，可确保部分剪接和未剪接转录本的表达。我们在 Rev 蛋白的精氨酸丰富基序 (ARM) 中鉴定出 ULM（UHM 配体基序）基序。ULM（UHM 配体基序）通过与 UHM（U2AF 同源基序）结构域结合，在剪接体组装过程中介导蛋白质相互作用。通过 NMR、生物物理方法和晶体学，我们表明 Rev ULM 结合到 U2AF65 和 SPF45 的 UHMs 上。Rev ULM 中高度保守的色氨酸 45 对于体外 UHM 结合、Rev 在人细胞中与 U2AF65 的共沉淀以及 HIV 转录本的正确加工至关重要。因此，Rev-ULM 与 UHM 剪接因子的相互作用有助于调节 HIV-1 转录本加工，也有助于剪接水平的调节。Rev ULM 是病毒模拟宿主短线性基序的一个例子，使病毒能够干扰宿主分子机制。
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