Fragile X mental retardation syndrome: structure of the KH1-KH2 domains of fragile X mental retardation protein.
Fragile X mental retardation syndrome: structure of the KH1-KH2 domains of fragile X mental retardation protein.
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DOI：
10.1016/j.str.2007.06.022
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发表时间：
2007-09
期刊：
影响因子：
5.7
通讯作者：
R. Valverde;I. Pozdnyakova;T. Kajander;Janani Venkatraman;L. Regan
中科院分区：
文献类型：
--
作者：
R. Valverde;I. Pozdnyakova;T. Kajander;Janani Venkatraman;L. Regan
脆性X染色体综合征是人类遗传性智力低下的最常见形式，估计患病率约为1/4000男性。尽管一些观察表明功能性脆性X智力迟钝蛋白（FMRP）的缺乏是脆性X综合征的潜在基础，但FMRP的结构和功能目前尚不清楚。在这里，我们展示了人FMRP串联KH结构域的X射线晶体结构，它揭示了KH 1和KH 2结构域的相对方向以及Ile 304残基的位置，Ile 304残基突变为Asn与特别严重的脆性X综合征的发病率相关。我们发现，Ile 304 Asn突变都扰乱了结构和不稳定的蛋白质。
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.