Patil Ashwini, Nakamura Haruki
Institute for Protein Research, Osaka University, 3-2 Yamadaoka, Suita, Osaka 565-0871, Japan; Bioinformatics Centre, University of Pune, Ganeshkhind Road, Pune 411007, India.
Institute for Protein Research, Osaka University, 3-2 Yamadaoka, Suita, Osaka 565-0871, Japan.
Biophysics (Nagoya-shi). 2007 Jul 21;3:27-35. doi: 10.2142/biophysics.3.27. eCollection 2007.
Hubs are highly connected proteins in a protein-protein interaction network. Previous work has implicated disordered domains and high surface charge as the properties significant in the ability of hubs to bind multiple proteins. While conformational flexibility of disordered domains plays an important role in the binding ability of large hubs, high surface charge is the dominant property in small hubs. In this study, we further investigate the role of the high surface charge in the binding ability of small hubs in the absence of disordered domains. Using multipole expansion, we find that the charges are highly distributed over the hub surfaces. Residue enrichment studies show that the charged residues in hubs are more prevalent on the exposed surface, with the exception of Arg, which is predominantly found at the interface, as compared to non-hubs. This suggests that the charged residues act primarily from the exposed surface rather than the interface to affect the binding ability of small hubs. They do this through (i) enhanced intra-molecular electrostatic interactions to lower the desolvation penalty, (ii) indirect long - range intermolecular interactions with charged residues on the partner proteins for better complementarity and electrostatic steering, and (iii) increased solubility for enhanced diffusion-controlled rate of binding. Along with Arg, we also find a high prevalence of polar residues Tyr, Gln and His and the hydrophobic residue Met at the interfaces of hubs, all of which have the ability to form multiple types of interactions, indicating that the interfaces of hubs are optimized to participate in multiple interactions.
在蛋白质-蛋白质相互作用网络中，中心节点是高度连接的蛋白质。先前的研究表明，无序结构域和高表面电荷是中心节点结合多种蛋白质能力的重要特性。虽然无序结构域的构象灵活性在大型中心节点的结合能力中起重要作用，但高表面电荷是小型中心节点的主要特性。在本研究中，我们进一步研究了在没有无序结构域的情况下，高表面电荷在小型中心节点结合能力中的作用。通过多极展开，我们发现电荷高度分布在中心节点表面。残基富集研究表明，与非中心节点相比，中心节点中的带电残基在暴露表面更为普遍，除了主要位于界面处的精氨酸。这表明带电残基主要从暴露表面而非界面起作用来影响小型中心节点的结合能力。它们通过以下方式实现这一点：（i）增强分子内静电相互作用以降低去溶剂化惩罚；（ii）与伴侣蛋白上的带电残基进行间接的长程分子间相互作用以实现更好的互补性和静电引导；（iii）增加溶解度以提高扩散控制的结合速率。除了精氨酸，我们还发现在中心节点的界面处，极性残基酪氨酸、谷氨酰胺和组氨酸以及疏水残基甲硫氨酸的出现频率很高，所有这些残基都具有形成多种类型相互作用的能力，这表明中心节点的界面经过优化以参与多种相互作用。
