Science for Life Laboratory, Department of Gene Technology, KTH Royal Institute of Technology, Tomtebodavägen 23A, SE-171 65 Solna, Sweden.
Department of Chemical Engineering, KTH Royal Institute of Technology, Teknikringen 42, SE-114 28 Stockholm, Sweden.
Structure. 2024 Nov 7;32(11):2160-2167.e2. doi: 10.1016/j.str.2024.08.016. Epub 2024 Sep 18.
Homorepeats are motifs with reiterations of the same amino acid. They are prevalent in proteins associated with diverse physiological functions but also linked to several pathologies. Structural characterization of homorepeats has remained largely elusive, primarily because they generally occur in the disordered regions or proteins. Here, we address this subject by combining structures derived from machine learning with conformational sampling through physics-based simulations. We find that hydrophobic homorepeats have a tendency to fold into structured secondary conformations, while hydrophilic ones predominantly exist in unstructured states. Our data show that the flexibility rendered by disorder is a critical component besides the chemical feature that drives homorepeats composition toward hydrophilicity. The formation of regular secondary structures also influences their solubility, as pathologically relevant homorepeats display a direct correlation between repeat expansion, induction of helicity, and self-assembly. Our study provides critical insights into the conformational landscape of protein homorepeats and their structure-activity relationship.
同源重复是指具有相同氨基酸重复的基序。它们普遍存在于与多种生理功能相关的蛋白质中，但也与多种病理学有关。同源重复的结构特征在很大程度上仍然难以捉摸，主要是因为它们通常存在于无序区或蛋白质中。在这里，我们通过将机器学习得到的结构与基于物理模拟的构象采样相结合来解决这个问题。我们发现，疏水性同源重复有倾向于折叠成结构二级构象，而亲水性同源重复则主要以无规则构象存在。我们的数据表明，除了促使同源重复组成向亲水性发展的化学特征外，无序所赋予的柔韧性也是一个关键组成部分。规则二级结构的形成也会影响它们的溶解度，因为与病理学相关的同源重复表现出重复扩展、螺旋诱导和自组装之间的直接相关性。我们的研究为蛋白质同源重复的构象景观及其结构-活性关系提供了重要的见解。
