Medical Research Council Laboratory of Molecular Biology, Protein and Nucleic Acid Chemistry Division, Cambridge, UK.
Nat Chem Biol. 2010 May;6(5):331-7. doi: 10.1038/nchembio.342. Epub 2010 Apr 4.
Cyclophilin A (CypA) is a ubiquitous cis-trans prolyl isomerase with key roles in immunity and viral infection. CypA suppresses T-cell activation through cyclosporine complexation and is required for effective HIV-1 replication in host cells. We show that CypA is acetylated in diverse human cell lines and use a synthetically evolved acetyllysyl-tRNA synthetase/tRNA(CUA) pair to produce recombinant acetylated CypA in Escherichia coli. We determined atomic-resolution structures of acetylated CypA and its complexes with cyclosporine and HIV-1 capsid. Acetylation markedly inhibited CypA catalysis of cis to trans isomerization and stabilized cis rather than trans forms of the HIV-1 capsid. Furthermore, CypA acetylation antagonized the immunosuppressive effects of cyclosporine by inhibiting the sequential steps of cyclosporine binding and calcineurin inhibition. Our results reveal that acetylation regulates key functions of CypA in immunity and viral infection and provide a general set of mechanisms by which acetylation modulates interactions to regulate cell function.
亲环素 A（CypA）是一种普遍存在的顺反式脯氨酰异构酶，在免疫和病毒感染中具有关键作用。CypA 通过与环孢素复合物抑制 T 细胞激活，并且是 HIV-1 在宿主细胞中有效复制所必需的。我们表明 CypA 在多种人类细胞系中被乙酰化，并使用合成进化的乙酰赖氨酸-tRNA 合成酶/tRNA(CUA) 对在大肠杆菌中产生重组乙酰化 CypA。我们确定了乙酰化 CypA 及其与环孢素和 HIV-1 衣壳复合物的原子分辨率结构。乙酰化显着抑制 CypA 顺式到反式异构化的催化作用，并稳定 cis 而不是 trans 形式的 HIV-1 衣壳。此外，CypA 乙酰化通过抑制环孢素结合和钙调神经磷酸酶抑制的顺序步骤，拮抗环孢素的免疫抑制作用。我们的结果表明，乙酰化调节 CypA 在免疫和病毒感染中的关键功能，并提供了一组普遍的机制，通过这些机制，乙酰化调节相互作用以调节细胞功能。
