Valverde Roberto, Pozdnyakova Irina, Kajander Tommi, Venkatraman Janani, Regan Lynne
Department of Molecular Biophysics and Biochemistry, Yale University, 266 Whitney Avenue, New Haven, CT 06520, USA.
Structure. 2007 Sep;15(9):1090-8. doi: 10.1016/j.str.2007.06.022.
Fragile X syndrome is the most common form of inherited mental retardation in humans, with an estimated prevalence of about 1 in 4000 males. Although several observations indicate that the absence of functional Fragile X Mental Retardation Protein (FMRP) is the underlying basis of Fragile X syndrome, the structure and function of FMRP are currently unknown. Here, we present an X-ray crystal structure of the tandem KH domains of human FMRP, which reveals the relative orientation of the KH1 and KH2 domains and the location of residue Ile304, whose mutation to Asn is associated with a particularly severe incidence of Fragile X syndrome. We show that the Ile304Asn mutation both perturbs the structure and destabilizes the protein.
脆性X综合征是人类遗传性智力障碍最常见的形式，据估计在男性中的患病率约为1/4000。尽管有多项观察表明，功能性脆性X智力障碍蛋白（FMRP）的缺失是脆性X综合征的潜在病因，但FMRP的结构和功能目前尚不清楚。在此，我们展示了人FMRP串联KH结构域的X射线晶体结构，该结构揭示了KH1和KH2结构域的相对取向以及残基Ile304的位置，Ile304突变为Asn与脆性X综合征的特别严重发病率相关。我们发现Ile304Asn突变既扰乱了结构又使蛋白质不稳定。
