脆性X染色體相關(guān)性震顫/共濟(jì)失調(diào)綜合癥(Fragile X tremor/ataxia syndrome,FXTAS)是一種常見的遺傳性神經(jīng)退行性疾病,。大多數(shù)FXTAS患者為男性，并在55歲之后,，患者會(huì)出現(xiàn)顫抖,，平衡不良及癡呆等明顯癥狀,。之前有研究表明，這種疾病是由于患者缺失一種Pur-α蛋白引起的,，該蛋白對(duì)正常神經(jīng)功能的發(fā)揮至關(guān)重要,。
最近，Ludwigs-Maximilians大學(xué)Dierk Niessing主持的課題組確定出Pur-α蛋白的三維結(jié)構(gòu),，并進(jìn)一步對(duì)該蛋白的分子功能進(jìn)行研究,。這項(xiàng)研究發(fā)表在最近一期的Proceedings of the National Academy of Sciences雜志上。
引起FXTAS的根本原因由于FMRP(Fragile X Mental Retardation Protein)發(fā)生突變,，該突變出現(xiàn)在X染色體上,，男性中的發(fā)病率為1/800，該病是由于X染色體DNA序列CGG三堿基重復(fù)序列異常增多引起,，正常人一般有5～54個(gè)CGG三堿基拷貝,，而FXTAS患者一般有55～200個(gè)CGG三堿基拷貝。當(dāng)機(jī)體缺乏Pur-α蛋白時(shí)也能引發(fā)FXTAS病癥,。Pur-α蛋白能夠結(jié)合到FMR的mRNA鏈上的CGG序列上,，當(dāng)FMRP mRNA上含有過量的CGG三堿基序列時(shí)，與之結(jié)合的Pur-α蛋白相應(yīng)增加,，因而使得維持細(xì)胞正常功能的Pur-α蛋白的量不足,。
研究人員利用小角度X-射線散射技術(shù)(small angle X-ray scattering)對(duì)Pur-α蛋白的三維結(jié)構(gòu)進(jìn)行分析發(fā)現(xiàn)，該蛋白由三個(gè)PUR repeat的結(jié)構(gòu)單元構(gòu)成,，其晶體結(jié)構(gòu)的發(fā)現(xiàn)將使科學(xué)家進(jìn)一步了解該蛋白的功能,，或?qū)⒂兄陂_發(fā)相應(yīng)的FXTAS治療方法。（生物谷Bioon.com）
生物谷推薦原始出處：
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.
