Essential role of coiled coils for aggregation and activity of Q/N-rich prions and PolyQ proteins.
Essential role of coiled coils for aggregation and activity of Q/N-rich prions and PolyQ proteins.
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DOI：
10.1016/j.cell.2010.11.042
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发表时间：
2010-12-23
期刊：
影响因子：
64.5
通讯作者：
Hendrickson WA
中科院分区：
文献类型：
--
作者：
Fiumara F;Fioriti L;Kandel ER;Hendrickson WA
富含谷氨酰胺/天冬酰胺（Q/N）的朊病毒的功能转换和polyQ-扩展蛋白的神经毒性涉及复杂的聚集倾向的结构转变，通常被认为是形成β-折叠。通过分析这些蛋白质的相互作用伙伴的序列，我们发现了经常存在的卷曲螺旋结构域的合作伙伴和侧翼或重叠的Q/N-丰富和polyQ域的片段。由于卷曲螺旋可以介导蛋白质相互作用和多聚化，我们研究了它们可能参与Q/N丰富和polyQ聚集。利用圆二色性和化学交联，我们发现富含Q/N的肽和polyQ肽在体外形成α-螺旋卷曲螺旋并组装成多聚体。使用结构指导的诱变，我们发现，卷曲螺旋结构域调节两个Q/N-丰富的朊病毒和polyQ-扩大亨廷顿蛋白的体内特性。破坏卷曲螺旋的突变损害聚集和活性，而增强卷曲螺旋倾向的突变促进聚集。这些发现支持了一个卷曲螺旋模型的功能开关的Q/N丰富的朊病毒和多Q-扩张疾病的发病机制。
The functional switch of glutamine/asparagine (Q/N)-rich prions and the neurotoxicity of polyQ-expanded proteins involve complex aggregation-prone structural transitions, commonly presumed to be forming β-sheets. By analyzing sequences of interaction partners of these proteins, we discovered a recurrent presence of coiled-coil domains both in the partners and in segments that flank or overlap Q/N-rich and polyQ domains. Since coiled-coils can mediate protein interactions and multimerization, we studied their possible involvement in Q/N-rich and polyQ aggregations. Using circular dichroism and chemical cross-linking, we found that Q/N-rich and polyQ peptides form α-helical coiled-coils in vitro and assemble into multimers. Using structure-guided mutagenesis, we found that coiled-coil domains modulate in vivo properties of two Q/N-rich prions and polyQ-expanded huntingtin. Mutations that disrupt coiled-coils impair aggregation and activity, whereas mutations that enhance coiled-coil propensity promote aggregation. These findings support a coiled-coil model for the functional switch of Q/N-rich prions and for the pathogenesis of polyQ-expansion diseases.
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DOI：
10.1016/j.str.2009.08.002
发表时间：
2009-09-09
期刊：
Structure (London, England : 1993)
影响因子：
--
作者：
Kim MW;Chelliah Y;Kim SW;Otwinowski Z;Bezprozvanny I
通讯作者：
Bezprozvanny I
影响因子：
3.5
作者：
Davies, Philippa;Watt, Kate;McEwan, Iain J.
通讯作者：
McEwan, Iain J.
影响因子：
2.2
作者：
Leitgeb, Balazs;Kerenyi, Adam;Rakhely, Gabor
通讯作者：
Rakhely, Gabor
影响因子：
3
作者：
Chang, DK;Cheng, SF;Lin, KL
通讯作者：
Lin, KL
影响因子：
64.8
作者：
Li, Y;Brown, JH;Cohen, C
通讯作者：
Cohen, C