Changes in the middle region of Sup35 profoundly alter the nature of epigenetic inheritance for the yeast prion [PSI+]
Changes in the middle region of Sup35 profoundly alter the nature of epigenetic inheritance for the yeast prion [PSI+]
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DOI：
10.1073/pnas.252652099
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发表时间：
2002-12-10
影响因子：
11.1
通讯作者：
Lindquist, SL
中科院分区：
文献类型：
--
作者：
Liu, JJ;Sondheimer, N;Lindquist, SL
酵母朊病毒[PSI +]通过蛋白质构象的自我延续变化为新表型的遗传提供了表观遗传机制。[PSI+]是翻译终止因子Sup35 p的非功能性有序聚集体，其影响newSup35蛋白采取相同的状态。Sup35p的N-末端区域在朊病毒的诱导和繁殖中起核心作用。C-末端区域提供翻译终止活性。高度带电的构象柔性中间区域（M）的功能是未知的。一个M缺失突变体能够以朊病毒或非朊病毒状态存在，但在任何一种情况下，它大多是不溶性的。用带电荷的合成多肽取代M恢复了可溶性，但由这种变体形成的朊病毒在有丝分裂中非常不稳定。用另外两种蛋白质的带电柔性区域取代M，产生了获得朊病毒状态（定义为从野生型[PSI +]元件转移到它们身上的功能的自我延续变化）的变体，但具有完全不同的性质。一个是可溶于朊病毒和非朊病毒的形式，有丝分裂稳定，但减数分裂不稳定，并治愈盐酸胍，但不能通过改变热休克蛋白104（HSP 104 p）。另一种只能在野生型蛋白存在下维持朊病毒状态，产生孟德尔分离模式。这些M变异体的独特特征，都携带相同的N-末端朊病毒决定区，证明了M对[PSI +]的重要性，并表明更广泛的表观遗传现象可能是基于自我延续，朊病毒样蛋白质构象的变化比我们目前定义朊病毒状态的方法所建议的。
The yeast prion [PSI+] provides an epigenetic mechanism for the inheritance of new phenotypes through self-perpetuating changes in protein conformation. [PSI+] is a nonfunctional, ordered aggregate of the translation termination factor Sup35p that influences newSup35 proteins to adopt the same state. The N-terminal region of Sup35p plays a central role in prion induction and propagation. The C-terminal region provides translation termination activity. The function of the highly charged, conformationally flexible middle region (M) is unknown. An M deletion mutant was capable of existing in either the prion or the nonprion state, but in either case it was mostly insoluble. Substituting a charged synthetic polypeptide for M restored solubility, but the prions formed by this variant were mitotically very unstable. Substituting charged flexible regions from two other proteins for M created variants that acquired prion states (defined as self-perpetuating changes in function transferred to them from wild-type [PSI+] elements), but had profoundly different properties. One was soluble in both the prion and the nonprion form, mitotically stable but meiotically unstable, and cured by guanidine HCl but not by alterations in heat shock protein 104 (Hsp104p). The other could only maintain the prion state in the presence of wild-type protein, producing Mendelian segregation patterns. The unique character of these M variants, all carrying the same N-terminal prion-determining region, demonstrate the importance of M for [PSI+] and suggest that a much wider range of epigenetic phenomena might be based on self-perpetuating, prion-like changes in protein conformation than suggested by our current methods for defining prion states.