2012年9月19日 訊 /生物谷BIOON/ --錯誤折疊的蛋白質(zhì)可以引發(fā)許多類型的神經(jīng)變性疾病,，如脊髓小腦共濟失調(diào)癥（SCAs）或者亨廷頓病,，這些疾病都是由于大腦中缺失發(fā)育中的神經(jīng)元所致。近日,，來自德國馬克斯-德爾布呂克分子醫(yī)學中心等機構的研究者識別出了21種蛋白質(zhì),，其可以特異性地結(jié)合到稱為ataxin-1的蛋白質(zhì)上發(fā)揮作用。其中12種蛋白質(zhì)可以增強ataxin-1的錯誤折疊,，隨后促進有害蛋白質(zhì)結(jié)構的形成,，而另外9種蛋白質(zhì)可以抑制ataxin-1錯誤折疊的行為,。相關研究成果刊登在了國際雜志PLoS Genetics上。
當?shù)鞍踪|(zhì)氨基酸鏈進行正常折疊時,，蛋白質(zhì)的功能就可以正常合適地進行發(fā)揮,。錯誤折疊的蛋白質(zhì)對于細胞是有害的，而且其可以和其它蛋白質(zhì)聚集形成不溶解的形式,，從而產(chǎn)生更強的毒害作用,。
研究者目前研究的Ataxin-1蛋白質(zhì)，其由于基因的缺失更易于錯誤折疊,，從而引發(fā)神經(jīng)變性疾病,。其產(chǎn)生錯誤折疊的原因是一種稱為谷氨酰胺的氨基酸在ataxin-1的氨基酸鏈中是重復存在的，氨基酸鏈中谷氨酰胺越多,，這種蛋白質(zhì)對細胞的毒性就越強,。40%以上的谷氨酰胺重復被認為是對細胞有害的,。
研究者發(fā)現(xiàn)了21種蛋白質(zhì),，其可以和ataxin-1進行反應，影響其折疊或者錯誤折疊,。其中12種蛋白質(zhì)可以增強其毒性,，而9種蛋白質(zhì)可以減少其錯誤折疊。
隨后研究者檢測了增強ataxin-1的蛋白質(zhì)的結(jié)構特征,，發(fā)現(xiàn)這些蛋白質(zhì)都存在一種特殊結(jié)構： 卷曲螺旋結(jié)構域結(jié)構(coiled-coil-domain),，因為這些蛋白質(zhì)都類似于雙螺旋結(jié)構，這種結(jié)構可以促使ataxin-1聚集,，從而增強其對細胞的毒力,。正如研究者所說，這種結(jié)構可以作為潛在的靶點,，未來科學家可以開發(fā)出靶向藥物來治療因ataxin-1錯誤折疊所引發(fā)的疾病。（生物谷Bioon.com）
編譯自：Neurodegenerative Diseases: New Findings On Protein Misfolding
doi:10.1371/journal.pgen.1002897
PMC:
PMID:
Identification of Human Proteins That Modify Misfolding and Proteotoxicity of Pathogenic Ataxin-1
Spyros Petrakis1#, Tamás Raskó1#, Jenny Russ1#, Ralf P. Friedrich1#, Martin Stroedicke1#, Sean-Patrick Riechers1, Katja Muehlenberg1, Angeli Möller1, Anita Reinhardt2, Arunachalam Vinayagam1, Martin H. Schaefer3, Michael Boutros4, Hervé Tricoire2, Miguel A. Andrade-Navarro3, Erich E. Wanker1*
Proteins with long, pathogenic polyglutamine (polyQ) sequences have an enhanced propensity to spontaneously misfold and self-assemble into insoluble protein aggregates. Here, we have identified 21 human proteins that influence polyQ-induced ataxin-1 misfolding and proteotoxicity in cell model systems. By analyzing the protein sequences of these modifiers, we discovered a recurrent presence of coiled-coil (CC) domains in ataxin-1 toxicity enhancers, while such domains were not present in suppressors. This suggests that CC domains contribute to the aggregation- and toxicity-promoting effects of modifiers in mammalian cells. We found that the ataxin-1–interacting protein MED15, computationally predicted to possess an N-terminal CC domain, enhances spontaneous ataxin-1 aggregation in cell-based assays, while no such effect was observed with the truncated protein MED15ΔCC, lacking such a domain. Studies with recombinant proteins confirmed these results and demonstrated that the N-terminal CC domain of MED15 (MED15CC) per se is sufficient to promote spontaneous ataxin-1 aggregation in vitro. Moreover, we observed that a hybrid Pum1 protein harboring the MED15CC domain promotes ataxin-1 aggregation in cell model systems. In strong contrast, wild-type Pum1 lacking a CC domain did not stimulate ataxin-1 polymerization. These results suggest that proteins with CC domains are potent enhancers of polyQ-mediated protein misfolding and aggregation in vitro and in vivo.
