Orr Asuka A, Shaykhalishahi Hamed, Mirecka Ewa A, Jonnalagadda Sai Vamshi R, Hoyer Wolfgang, Tamamis Phanourios
Artie McFerrin Department of Chemical Engineering, Texas A&M University, College Station, Texas 77843-3122, United States.
Institut für Physikalische Biologie, Heinrich-Heine-Universität Düsseldorf, Düsseldorf 40204, Germany.
Comput Chem Eng. 2018 Aug 4;116:322-332. doi: 10.1016/j.compchemeng.2018.02.013. Epub 2018 Feb 21.
-wrapins are engineered binding proteins stabilizing the -hairpin conformations of amyloidogenic proteins islet amyloid polypeptide (IAPP), amyloid-, and -synuclein, thus inhibiting their amyloid propensity. Here, we use computational and experimental methods to investigate the molecular recognition of IAPP by -wrapins. We show that the multi-targeted, IAPP, amyloid-, and -synuclein, binding properties of -wrapins originate mainly from optimized interactions between -wrapin residues and sets of residues in the three amyloidogenic proteins with similar physicochemical properties. Our results suggest that IAPP is a comparatively promiscuous -wrapin target, probably due to the low number of charged residues in the IAPP -hairpin motif. The sub-micromolar affinity of -wrapin HI18, specifically selected against IAPP, is achieved in part by salt-bridge formation between HI18 residue Glu10 and the IAPP N-terminal residue Lys1, both located in the flexible N-termini of the interacting proteins. Our findings provide insights towards developing novel protein-based single- or multi-targeted therapeutics.
包裹蛋白是经过工程设计的结合蛋白，可稳定胰岛淀粉样多肽（IAPP）、淀粉样β蛋白和α-突触核蛋白等淀粉样蛋白的β-发夹构象，从而抑制它们形成淀粉样蛋白的倾向。在此，我们使用计算和实验方法来研究包裹蛋白对IAPP的分子识别。我们表明，包裹蛋白对IAPP、淀粉样β蛋白和α-突触核蛋白的多靶点结合特性主要源于包裹蛋白残基与三种淀粉样蛋白中具有相似物理化学性质的残基组之间的优化相互作用。我们的结果表明，IAPP可能是一个相对较为“混杂”的包裹蛋白靶点，这可能是由于IAPP的β-发夹基序中带电荷的残基数量较少。专门针对IAPP筛选出的包裹蛋白HI18的亚微摩尔亲和力，部分是通过HI18残基Glu10与IAPP N端残基Lys1之间形成盐桥实现的，这两个残基都位于相互作用蛋白的柔性N端。我们的研究结果为开发新型基于蛋白质的单靶点或多靶点疗法提供了见解。
