脆性X染色体相关性震颤/共济失调综合症(Fragile X tremor/ataxia syndrome,FXTAS)是一种常见的遗传性神经退行性疾病。大多数FXTAS患者为男性，并在55岁之后，患者会出现颤抖，平衡不良及痴呆等明显症状。之前有研究表明，这种疾病是由于患者缺失一种Pur-α蛋白引起的，该蛋白对正常神经功能的发挥至关重要。
最近，Ludwigs-Maximilians大学Dierk Niessing主持的课题组确定出Pur-α蛋白的三维结构，并进一步对该蛋白的分子功能进行研究。这项研究发表在最近一期的Proceedings of the National Academy of Sciences杂志上。
引起FXTAS的根本原因由于FMRP(Fragile X Mental Retardation Protein)发生突变，该突变出现在X染色体上，男性中的发病率为1/800，该病是由于X染色体DNA序列CGG三碱基重复序列异常增多引起，正常人一般有5～54个CGG三碱基拷贝，而FXTAS患者一般有55～200个CGG三碱基拷贝。当机体缺乏Pur-α蛋白时也能引发FXTAS病症。Pur-α蛋白能够结合到FMR的mRNA链上的CGG序列上，当FMRP mRNA上含有过量的CGG三碱基序列时，与之结合的Pur-α蛋白相应增加，因而使得维持细胞正常功能的Pur-α蛋白的量不足。
研究人员利用小角度X-射线散射技术(small angle X-ray scattering)对Pur-α蛋白的三维结构进行分析发现，该蛋白由三个PUR repeat的结构单元构成，其晶体结构的发现将使科学家进一步了解该蛋白的功能，或将有助于开发相应的FXTAS治疗方法。（生物谷Bioon.com）
生物谷推荐原始出处：
PNAS October 21, 2009, doi: 10.1073/pnas.0907990106
X-ray structure of Pur-α reveals a Whirly-like fold and an unusual nucleic-acid binding surface
Almut Graebscha,b, Stéphane Rochea,b and Dierk Niessinga,b,1
aInstitute of Structural Biology, Helmholtz Zentrum München, German Research Center for Environmental Health, Marchionini-Strasse 25, Munich, 81377, Germany; and
bDepartment of Chemistry and Biochemistry, Gene Center Munich and Center for Integrated Protein Science CIPSM, Ludwig-Maximilians-University Munich, Feodor-Lynen-Strasse 25, Munich, 81377, Germany
The PUR protein family is a distinct and highly conserved class that is characterized by its sequence-specific RNA- and DNA-binding. Its best-studied family member, Pur-α, acts as a transcriptional regulator, as host factor for viral replication, and as cofactor for mRNP localization in dendrites. Pur-α-deficient mice show severe neurologic defects and die after birth. Nucleic-acid binding by Pur-α is mediated by its central core region, for which no structural information is available. We determined the x-ray structure of residues 40 to 185 from Drosophila melanogaster Pur-α, which constitutes a major part of the core region. We found that this region contains two almost identical structural motifs, termed “PUR repeats,” which interact with each other to form a PUR domain. DNA- and RNA-binding studies confirmed that PUR domains are indeed functional nucleic-acid binding domains. Database analysis show that PUR domains share a fold with the Whirly class of nucleic-acid binding proteins. Structural analysis combined with mutational studies suggest that a PUR domain binds nucleic acids through two independent surface regions involving concave β-sheets. Structure-based sequence alignment revealed that the core region harbors a third PUR repeat at its C terminus. Subsequent characterization by small-angle x-ray scattering (SAXS) and size- exclusion chromatography indicated that PUR repeat III mediates dimerization of Pur-α. Surface envelopes calculated from SAXS data show that the Pur-α dimer consisting of repeats I to III is arranged in a Z-like shape. This unexpected domain organization of the entire core domain of Pur-α has direct implications for ssDNA/ssRNA and dsDNA binding.
