巴塞羅那自治大學(xué)(UAB)的研究人員發(fā)現(xiàn)，某些蛋白質(zhì)即使折疊正確,，但仍然能夠?qū)е露喾N蛋白質(zhì)構(gòu)象病,，如肌萎縮性側(cè)索硬化癥(amyotrophic lateral sclerosis),，家族性淀粉樣心肌病(familial amyloidotic cardiomyopathy)等,。
研究人員對(duì)這些蛋白質(zhì)各個(gè)亞基的三維結(jié)構(gòu)進(jìn)行分析，最終發(fā)現(xiàn)了答案所在——這些蛋白質(zhì)通常是由兩個(gè)或兩個(gè)以上的亞基構(gòu)成,，即使蛋白質(zhì)折疊正確,，如果各亞基在組合過程中發(fā)生突變，同樣能使該蛋白質(zhì)成為毒性大分子淀粉體纖維(amyloid fibrils),。這項(xiàng)研究發(fā)表在近期的PLoS Computational Biology,。
蛋白質(zhì)聚集和錯(cuò)誤折疊與一些遺傳性或自發(fā)性的構(gòu)象類疾病相關(guān)。蛋白質(zhì)聚集成球狀蛋白將導(dǎo)致肝臟,，心臟,，腎臟和神經(jīng)疾病。研究人員通過計(jì)算機(jī)分析,，發(fā)現(xiàn)在非病理?xiàng)l件下,，與構(gòu)象疾病相關(guān)的球狀蛋白是成對(duì)連接到其他蛋白或亞基復(fù)合體中。在連接過程中,，蛋白易聚集區(qū)域(aggregation-prone regions)相互覆蓋,，這樣就防止易聚集區(qū)外露引起蛋白質(zhì)聚集。但研究人員發(fā)現(xiàn),，若連接的區(qū)域發(fā)生突變,，將阻止連接發(fā)生，并形成毒性大分子聚集物,。
因此,，為了阻止蛋白質(zhì)之間的解離，研究人員打算引入一種能使蛋白質(zhì)之間加強(qiáng)聯(lián)系的基因突變，并開發(fā)一種特異性阻斷已解離區(qū)域相互聚集的大分子,。（生物谷Bioon.com）
生物谷推薦原始出處：
PLoS Comput Biol 5(8): e1000476. doi:10.1371/journal.pcbi.1000476
Amyloidogenic Regions and Interaction Surfaces Overlap in Globular Proteins Related to Conformational Diseases
Virginia Castillo, Salvador Ventura*
Departament de Bioquímica i Biologia Molecular and Institut de Biotecnologia i de Biomedicina, Universitat Autònoma de Barcelona, Barcelona, Spain
Protein aggregation underlies a wide range of human disorders. The polypeptides involved in these pathologies might be intrinsically unstructured or display a defined 3D-structure. Little is known about how globular proteins aggregate into toxic assemblies under physiological conditions, where they display an initially folded conformation. Protein aggregation is, however, always initiated by the establishment of anomalous protein-protein interactions. Therefore, in the present work, we have explored the extent to which protein interaction surfaces and aggregation-prone regions overlap in globular proteins associated with conformational diseases. Computational analysis of the native complexes formed by these proteins shows that aggregation-prone regions do frequently overlap with protein interfaces. The spatial coincidence of interaction sites and aggregating regions suggests that the formation of functional complexes and the aggregation of their individual subunits might compete in the cell. Accordingly, single mutations affecting complex interface or stability usually result in the formation of toxic aggregates. It is suggested that the stabilization of existing interfaces in multimeric proteins or the formation of new complexes in monomeric polypeptides might become effective strategies to prevent disease-linked aggregation of globular proteins.
