Nova KH 结构域对序列特异性 RNA 的结合：对副肿瘤性疾病和脆性 X 综合征的影响。

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

作者信息

Lewis H A, Musunuru K, Jensen K B, Edo C, Chen H, Darnell R B, Burley S K

机构信息

Laboratories of Molecular Biophysics, The Rockefeller University, New York, New York 10021, USA.

出版信息

Cell. 2000 Feb 4;100(3):323-32. doi: 10.1016/s0092-8674(00)80668-6.

DOI:10.1016/s0092-8674(00)80668-6

PMID:10676814

Abstract

The structure of a Nova protein K homology (KH) domain recognizing single-stranded RNA has been determined at 2.4 A 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.

摘要

已确定一种识别单链RNA的诺瓦蛋白K同源（KH）结构域在2.4埃分辨率下的结构。哺乳动物诺瓦抗原（1和2）构成神经元中RNA代谢的一个重要调节因子家族，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结合的诺瓦-2的第三个KH结构域（KH3）的结构类似于一个分子虎钳，5'-尿嘧啶-胞嘧啶-腺嘌呤-胞嘧啶-3'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肪族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智力障碍是由FMR1蛋白对RNA结合的干扰导致的。