Sequence-specific RNA binding by a Nova KH domain: Implications for paraneoplastic disease and the fragile X syndrome

The structure of a Nova protein K homology (KH) domain recognizing single-stranded RNA has been determined at 2.4 Angstrom resolution. Mammalian Nova antigens (1 and 2) constitute an important family of regulators of RNA metabolism in neurons, first identified using sera from cancer patients with the autoimmune disorder paraneoplastic opsoclonus-myoclonus ataxia (POMA). The structure of the third KH domain (KH3) of Nova-2 bound to a stem loop RNA resembles a molecular vise, with 5'-Ura-Cyt-Ade-Cyt-3' pinioned between an invariant Gly-X-X-Gly motif and the variable loop. Tetranucleotide recognition is supported by an aliphatic alpha helix/beta sheet RNA-binding platform, which mimics 5'-Ura-Gua-3' by making Watson-Crick-like hydrogen bonds with 5'-Cyt-Ade-3'. Sequence conservation suggests that fragile X mental retardation results from perturbation of RNA binding by the FMR1 protein.

一种识别单链RNA的Nova蛋白K同源（KH）结构域的结构已在2.4埃分辨率下被确定。哺乳动物Nova抗原（1和2）构成了神经元中RNA代谢调节因子的一个重要家族，最初是使用患有自身免疫性疾病副肿瘤性眼阵挛 - 肌阵挛性共济失调（POMA）的癌症患者的血清鉴定出来的。与茎环RNA结合的Nova - 2的第三个KH结构域（KH3）的结构类似于一个分子钳，5' - 尿嘧啶 - 胞嘧啶 - 腺嘌呤 - 胞嘧啶 - 3'被夹在一个不变的甘氨酸 - X - X - 甘氨酸基序和可变环之间。四核苷酸识别由一个脂族α螺旋/β折叠RNA结合平台支持，该平台通过与5' - 胞嘧啶 - 腺嘌呤 - 3'形成类似沃森 - 克里克的氢键来模拟5' - 尿嘧啶 - 鸟嘌呤 - 3'。序列保守性表明，脆性X智力低下是由FMR1蛋白对RNA结合的干扰导致的。