2012年9月19日 訊 /生物谷BIOON/ --錯誤摺疊的蛋白質可以引發許多類型的神經變性疾病，如脊髓小腦共濟失調症（SCAs）或者亨廷頓病，這些疾病都是由於大腦中缺失發育中的神經元所致。近日，來自德國馬克斯-德爾布呂克分子醫學中心等機構的研究者識別出了21種蛋白質，其可以特異性地結合到稱為ataxin-1的蛋白質上發揮作用。其中12種蛋白質可以增強ataxin-1的錯誤摺疊，隨後促進有害蛋白質結構的形成，而另外9種蛋白質可以抑制ataxin-1錯誤摺疊的行為。相關研究成果刊登在了國際雜誌PLoS Genetics上。
當蛋白質胺基酸鏈進行正常摺疊時，蛋白質的功能就可以正常合適地進行發揮。錯誤摺疊的蛋白質對於細胞是有害的，而且其可以和其它蛋白質聚集形成不溶解的形式，從而產生更強的毒害作用。
研究者目前研究的Ataxin-1蛋白質，其由於基因的缺失更易於錯誤摺疊，從而引發神經變性疾病。其產生錯誤摺疊的原因是一種稱為穀氨醯胺的胺基酸在ataxin-1的胺基酸鏈中是重複存在的，胺基酸鏈中穀氨醯胺越多，這種蛋白質對細胞的毒性就越強。40%以上的穀氨醯胺重複被認為是對細胞有害的。
研究者發現了21種蛋白質，其可以和ataxin-1進行反應，影響其摺疊或者錯誤摺疊。其中12種蛋白質可以增強其毒性，而9種蛋白質可以減少其錯誤摺疊。
隨後研究者檢測了增強ataxin-1的蛋白質的結構特徵，發現這些蛋白質都存在一種特殊結構： 捲曲螺旋結構域結構(coiled-coil-domain)，因為這些蛋白質都類似於雙螺旋結構，這種結構可以促使ataxin-1聚集，從而增強其對細胞的毒力。正如研究者所說，這種結構可以作為潛在的靶點，未來科學家可以開發出靶向藥物來治療因ataxin-1錯誤摺疊所引發的疾病。（生物谷Bioon.com）
編譯自：Neurodegenerative Diseases: New Findings On Protein Misfolding
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.