Switch Laboratory, VIB Center for Brain and Disease Research, Leuven, Belgium; Department for Cellular and Molecular Medicine, KU Leuven, Herestraat 49, 3000 Leuven, Belgium.
Switch Laboratory, VIB Center for Brain and Disease Research, Leuven, Belgium; Department for Cellular and Molecular Medicine, KU Leuven, Herestraat 49, 3000 Leuven, Belgium.
Structure. 2022 Aug 4;30(8):1178-1189.e3. doi: 10.1016/j.str.2022.05.002. Epub 2022 May 23.
The increasing number of amyloid structures offers an opportunity to investigate the general principles determining amyloid stability and polymorphism. We find that amyloid stability is dominated by ∼30% of residues localized in segments that favor the cross-β conformation. These correspond to known aggregation-nucleating regions and constitute a stabilizing cross-β structural framework that is shared among polymorphs. Alternative packing of these segments with structurally frustrated regions within the protofilament results in conformationally different, but energetically similar, polymorphs. Differential analysis of distributions of interatomic distances in amyloid and globular structures revealed that unconventional residue contacts, such as identical charges in close proximity, are located in energetically frustrated segments of amyloids. These observations suggest that polymorphism results from a framework mechanism consisting of conserved stabilizing regions of high cross-β propensity. These are interspersed by structurally suboptimal regions that are potential sites of conformational plasticity and interaction with stabilizing cofactors such as (poly)ions.
越来越多的淀粉样结构为研究决定淀粉样稳定性和多态性的一般原则提供了机会。我们发现，淀粉样稳定性主要由局部化在有利于交叉-β构象的片段中的约 30%的残基决定。这些片段对应于已知的聚集核区域，并构成了在多态体中共享的稳定的交叉-β结构框架。这些片段与原纤维内结构受阻区域的替代包装导致构象不同但能量相似的多态体。对淀粉样和球状结构中原子间距离分布的差异分析表明，非常规的残基接触，如近距离的相同电荷，位于淀粉样的能量受阻片段中。这些观察结果表明，多态性是由一个框架机制引起的，该机制由高交叉-β倾向的保守稳定区域组成。这些区域由结构上非最优的区域间隔开，这些区域是构象灵活性和与稳定辅助因子（如多离子）相互作用的潜在位点。
