Opposing effects of glutamine and asparagine govern prion formation by intrinsically disordered proteins.
Opposing effects of glutamine and asparagine govern prion formation by intrinsically disordered proteins.
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DOI：
10.1016/j.molcel.2011.05.013
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发表时间：
2011-07-08
期刊：
影响因子：
16
通讯作者：
Lindquist S
中科院分区：
文献类型：
--
作者：
Halfmann R;Alberti S;Krishnan R;Lyle N;O'Donnell CW;King OD;Berger B;Pappu RV;Lindquist S
富含谷氨酰胺(Q)和天冬酰胺(N)残基的序列通常不能在单体水平上折叠。这一点，再加上它们不同寻常的氢键能力，提供了在无序单体和淀粉样蛋白之间切换的动力。这样的转变控制着各种各样的过程，如人类蛋白质折叠疾病、细菌生物膜组装和酵母蛋白基因元件(基于蛋白质的遗传元件)的遗传。对蛋白形成结构域的系统研究表明，Q和N残基对淀粉样蛋白的形成有不同的影响。在这里，我们使用细胞生物学、生化和计算技术来比较富含Q/N的蛋白质变体，用Qs代替NS，用NS代替Qs。我们发现这两个残基具有强烈的相反的影响：N-富集度促进良性自模板淀粉样蛋白的组装；Q-富集性促进有毒的非淀粉样蛋白构象的形成。分子模拟集中在Qs和NS之间的内在折叠差异，表明它们不同的行为是由于NS比Qs更容易形成转角。
Sequences rich in glutamine (Q) and asparagine (N) residues often fail to fold at the monomer level. This, coupled to their unusual hydrogen-bonding abilities, provides the driving force to switch between disordered monomers and amyloids. Such transitions govern processes as diverse as human protein-folding diseases, bacterial biofilm assembly, and the inheritance of yeast prions (protein-based genetic elements). A systematic survey of prion-forming domains suggested that Q and N residues have distinct effects on amyloid formation. Here we use cell biological, biochemical, and computational techniques to compare Q/N-rich protein variants, replacing Ns with Qs and Qs with Ns. We find that the two residues have strong and opposing effects: N-richness promotes assembly of benign self-templating amyloids; Q-richness promotes formation of toxic non-amyloid conformers. Molecular simulations focusing on intrinsic folding differences between Qs and Ns suggest that their different behaviors are due to the enhanced turn-forming propensity of Ns over Qs.
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DOI：
10.1002/prot.340090104
发表时间：
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