Institut de Biotecnologia i de Biomedicina and Departament de Bioquímica i Biologia Molecular, Universitat Autónoma de Barcelona, Bellaterra, 08193, Spain.
Bioinformatics and Genomics Programme, Centre for Genomic Regulation (CRG), The Barcelona Institute for Science and Technology, Dr. Aiguader 88, 08003, Barcelona, Spain.
Sci Rep. 2017 Sep 21;7(1):12134. doi: 10.1038/s41598-017-09714-z.
Prion-like behaviour is attracting much attention due to the growing evidences that amyloid-like self-assembly may reach beyond neurodegeneration and be a conserved functional mechanism. The best characterized functional prions correspond to a subset of yeast proteins involved in translation or transcription. Their conformational promiscuity is encoded in Prion Forming Domains (PFDs), usually long and intrinsically disordered protein segments of low complexity. The compositional bias of these regions seems to be important for the transition between soluble and amyloid-like states. We have proposed that the presence of cryptic soft amyloid cores embedded in yeast PFDs can also be important for their assembly and demonstrated their existence and self-propagating abilities. Here, we used an orthogonal approach in the search of human domains that share yeast PFDs compositional bias and exhibit a predicted nucleating core, identifying 535 prion-like candidates. We selected seven proteins involved in transcriptional or translational regulation and associated to disease to characterize the properties of their amyloid cores. All of them self-assemble spontaneously into amyloid-like structures able to propagate their polymeric state. This provides support for the presence of short sequences able to trigger conformational conversion in prion-like human proteins, potentially regulating their functionality.
类朊病毒行为引起了广泛关注，因为越来越多的证据表明，淀粉样自组装可能超出神经退行性变的范围，成为一种保守的功能机制。功能最明确的类朊病毒对应于一组参与翻译或转录的酵母蛋白。它们的构象混杂性编码在朊病毒形成结构域（PFDs）中，通常是长的、固有无序的低复杂度蛋白质片段。这些区域的组成偏向似乎对于可溶性和淀粉样状态之间的转变很重要。我们提出，在酵母 PFDs 中嵌入的隐藏的柔软淀粉样核心的存在对于它们的组装也很重要，并证明了它们的存在和自我传播能力。在这里，我们在寻找具有酵母 PFDs 组成偏向并表现出预测的成核核心的人类结构域的正交方法中，鉴定了 535 个类朊病毒候选物。我们选择了七个参与转录或翻译调节且与疾病相关的蛋白质来表征其淀粉样核心的性质。它们都能自发地自我组装成能够传播其聚合物状态的淀粉样结构。这为存在能够在类朊病毒人类蛋白中引发构象转换的短序列提供了支持，可能调节它们的功能。
