The human ribosome-associated complex suppresses prion formation in yeast.
The human ribosome-associated complex suppresses prion formation in yeast.
复制标题
作者：
许多人类疾病与淀粉样蛋白的错误折叠有关。因此，了解细胞用来确保蛋白质组完整性的机制是开发潜在治疗干预措施的关键一步。酵母细胞拥有大量能够采用淀粉样蛋白构象的PrP形成蛋白，这可能是一种表观遗传机制，以应对不断变化的环境条件。核糖体相关复合体(RAC)停靠在核糖体多肽出口隧道附近，并招募Hsp70 SSB作为新生链的伴侣，可以调节酵母中这些淀粉样构象的获得。在这里，我们检测了在缺乏内源RAC的酵母中，人RAC伴侣蛋白Mpp11和Hsp70L1取代其酵母RAC同源蛋白Zuo1和Ssz1的能力，并调查了人类同源蛋白在酵母中执行RAC伴侣活性的程度。我们发现，Mpp11/Hsp70L1复合体可以部分纠正RAC缺陷酵母细胞的生长缺陷，尽管酵母/人类异种复合体在这一能力上是不同的。在没有RAC的情况下，Sup35蛋白自发转化为[PSI+]Prion构象的细胞比例因人RAC复合体的存在而减少。然而，表达致病扩展的多聚Q蛋白在酵母中的毒性不能被人类RAC伴侣所抵消。这个酵母系统可以作为一个简单的模型来研究人类RAC伴侣蛋白在多大程度上有助于对抗其他哺乳动物疾病相关蛋白的共翻译错误折叠。
Many human diseases are associated with the misfolding of amyloidogenic proteins. Understanding the mechanisms cells employ to ensure the integrity of the proteome is therefore a crucial step in the development of potential therapeutic interventions. Yeast cells possess numerous prion-forming proteins capable of adopting amyloid conformations, possibly as an epigenetic mechanism to cope with changing environmental conditions. The ribosome-associated complex (RAC), which docks near the ribosomal polypeptide exit tunnel and recruits the Hsp70 Ssb to chaperone nascent chains, can moderate the acquisition of these amyloid conformations in yeast. Here we examine the ability of the human RAC chaperone proteins Mpp11 and Hsp70L1 to function in place of their yeast RAC orthologues Zuo1 and Ssz1 in yeast lacking endogenous RAC and investigate the extent to which the human orthologues can perform RAC chaperone activities in yeast. We found that the Mpp11/Hsp70L1 complex can partially correct the growth defect seen in RAC-deficient yeast cells, although yeast/human hetero species complexes were variable in this ability. The proportion of cells in which the Sup35 protein undergoes spontaneous conversion to a [PSI+] prion conformation, which is increased in the absence of RAC, was reduced by the presence of the human RAC complex. However, the toxicity in yeast from expression of a pathogenically expanded polyQ protein was unable to be countered by the human RAC chaperones. This yeast system can serve as a facile model for studying the extent to which the human RAC chaperones contribute to combating cotranslational misfolding of other mammalian disease-associated proteins.
登录
查看更多内容
影响因子：
62.1
作者：
Nguyen PH;Ramamoorthy A;Sahoo BR;Zheng J;Faller P;Straub JE;Dominguez L;Shea JE;Dokholyan NV;De Simone A;Ma B;Nussinov R;Najafi S;Ngo ST;Loquet A;Chiricotto M;Ganguly P;McCarty J;Li MS;Hall C;Wang Y;Miller Y;Melchionna S;Habenstein B;Timr S;Chen J;Hnath B;Strodel B;Kayed R;Lesné S;Wei G;Sterpone F;Doig AJ;Derreumaux P
通讯作者：
Derreumaux P
影响因子：
56.9
作者：
Hundley, HA;Walter, W;Craig, EA
通讯作者：
Craig, EA
DOI：
10.1073/pnas.0504400102
发表时间：
2005-07-19
影响因子：
11.1
作者：
Otto, H;Conz, C;Rospert, S
通讯作者：
Rospert, S
DOI：
10.1083/jcb.200112104
发表时间：
2002-06-10
期刊：
The Journal of cell biology
影响因子：
--
作者：
Meriin AB;Zhang X;He X;Newnam GP;Chernoff YO;Sherman MY
通讯作者：
Sherman MY
OpenCFU，一种新的免费和开源软件，可计算细胞菌落和其他圆形对象。
影响因子：
3.7
作者：
Geissmann Q
通讯作者：
Geissmann Q