Biomolecular NMR Spectroscopy Laboratory, Department of Biosciences and Bioengineering, IIT Bombay, Powai, Maharashtra, India.
Nups and SUMO Biology Group, Department of Biological Sciences, IISER Bhopal, Bhopal, Madhya Pradesh, India.
Biophys J. 2022 Apr 19;121(8):1367-1380. doi: 10.1016/j.bpj.2022.03.022. Epub 2022 Mar 21.
The endoparasitic pathogen, Plasmodium falciparum (Pf), modulates protein-protein interactions to employ post-translational modifications like SUMOylation to establish successful infections. The interaction between E1 and E2 (Ubc9) enzymes governs species specificity in the Plasmodium SUMOylation pathway. Here, we demonstrate that a unidirectional cross-species interaction exists between Pf-SUMO and human E2, whereas Hs-SUMO1 failed to interact with Pf-E2. Biochemical and biophysical analyses revealed that surface-accessible aspartates of Pf-SUMO determine the efficacy and specificity of SUMO-Ubc9 interactions. Furthermore, we demonstrate that critical residues of the Pf-Ubc9 N terminus are responsible for diminished Hs-SUMO1 and Pf-Ubc9 interaction. Mutating these residues to corresponding Hs-Ubc9 residues restores electrostatic, π-π, and hydrophobic interactions and allows efficient cross-species interactions. We suggest that, in comparison with human counterparts, Plasmodium SUMO and Ubc9 proteins have acquired critical changes on their surfaces as nodes, which Plasmodium can use to exploit the host SUMOylation machinery.
内寄生病原体疟原虫（Pf）调节蛋白-蛋白相互作用，采用翻译后修饰（如 SUMO 化）来建立成功的感染。E1 和 E2（Ubc9）酶之间的相互作用控制着疟原虫 SUMO 化途径中的物种特异性。在这里，我们证明 Pf-SUMO 与人类 E2 之间存在单向种间相互作用，而 Hs-SUMO1 未能与 Pf-E2 相互作用。生化和生物物理分析表明，Pf-SUMO 的表面可及天冬氨酸决定了 SUMO-Ubc9 相互作用的效力和特异性。此外，我们证明 Pf-Ubc9 N 端的关键残基负责降低 Hs-SUMO1 和 Pf-Ubc9 相互作用。将这些残基突变为相应的 Hs-Ubc9 残基可以恢复静电、π-π 和疏水性相互作用，并允许有效的种间相互作用。我们认为，与人类对应物相比，疟原虫 SUMO 和 Ubc9 蛋白在其表面获得了作为节点的关键变化，疟原虫可以利用这些节点来利用宿主 SUMO 化机制。
