Division of Theoretical Chemistry, Department of Chemistry, Lund University, P.O. Box 124, SE-221 00 Lund, Sweden.
Structural Biology and NMR Laboratory, The Linderstrøm-Lang Centre for Protein Science and Integrative Structural Biology at University of Copenhagen (ISBUC), Department of Biology, University of Copenhagen, 2200 Copenhagen N, Denmark.
Biomolecules. 2019 Apr 30;9(5):168. doi: 10.3390/biom9050168.
Intrinsically disordered proteins (IDPs) can form functional oligomers and in some cases, insoluble disease related aggregates. It is therefore vital to understand processes and mechanisms that control pathway distribution. Divalent cations including Zn can initiate IDP oligomerisation through the interaction with histidine residues but the mechanisms of doing so are far from understood. Here we apply a multi-disciplinary approach using small angle X-ray scattering, nuclear magnetic resonance spectroscopy, calorimetry and computations to show that that saliva protein Histatin 5 forms highly dynamic oligomers in the presence of Zn. The process is critically dependent upon interaction between Zn ions and distinct histidine rich binding motifs which allows for thermodynamic switching between states. We propose a molecular mechanism of oligomerisation, which may be generally applicable to other histidine rich IDPs. Finally, as Histatin 5 is an important saliva component, we suggest that Zn induced oligomerisation may be crucial for maintaining saliva homeostasis.
无规卷曲蛋白 (IDP) 可以形成功能性寡聚体，在某些情况下，还会形成不溶性的与疾病相关的聚集体。因此，了解控制途径分布的过程和机制至关重要。二价阳离子（包括 Zn）可以通过与组氨酸残基相互作用来引发 IDP 寡聚化，但具体的作用机制还远未被理解。在这里，我们应用多学科方法，使用小角度 X 射线散射、核磁共振波谱学、量热法和计算来表明唾液蛋白Histatin 5 在 Zn 存在下形成高度动态的寡聚体。该过程严重依赖于 Zn 离子与不同富含组氨酸的结合模体之间的相互作用，这使得状态之间可以进行热力学切换。我们提出了一种寡聚化的分子机制，该机制可能适用于其他富含组氨酸的 IDP。最后，由于 Histatin 5 是唾液中的重要成分，我们认为 Zn 诱导的寡聚化可能对维持唾液内环境稳定至关重要。
