Limits...
The role of charged surface residues in the binding ability of small hubs in protein-protein interaction networks

View Article: PubMed Central - PubMed

ABSTRACT

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.

No MeSH data available.


Related in: MedlinePlus

Selected views of Arginine participating in various types of interactions in different binding orientations. (A) Arg42 of Ubiquitin (blue) participating in a salt bridge with Asp444 of the CUE domain of Vacuolar protein sorting-associated protein VPS9 (orange). The dihedral angle, CG-CD-NE-CZ, of Arg42 is 131.9 degrees. (PDB ID: 1P3Q). (B) Arg42 of Ubiquitin (blue) forming a hydrogen bond with Gly47 backbone (distance 2.8 Å) of Tumor susceptibility gene 101 protein TSG101 (orange). The dihedral angle, CG-CD-NE-CZ, of Arg42 is −143.4 degrees. (PDB ID: 1S1Q). (C) Arg73 of Son Of Sevenless-1 (blue) participating in a cation-π interaction with Tyr884 of H-RAS (orange). The dihedral angle, CG-CD-NE-CZ, of Arg73 is 124.2 degrees. (PDB ID: 1BKD) Figure created using jV 3.212.
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC5036656&req=5

f5-3_27: Selected views of Arginine participating in various types of interactions in different binding orientations. (A) Arg42 of Ubiquitin (blue) participating in a salt bridge with Asp444 of the CUE domain of Vacuolar protein sorting-associated protein VPS9 (orange). The dihedral angle, CG-CD-NE-CZ, of Arg42 is 131.9 degrees. (PDB ID: 1P3Q). (B) Arg42 of Ubiquitin (blue) forming a hydrogen bond with Gly47 backbone (distance 2.8 Å) of Tumor susceptibility gene 101 protein TSG101 (orange). The dihedral angle, CG-CD-NE-CZ, of Arg42 is −143.4 degrees. (PDB ID: 1S1Q). (C) Arg73 of Son Of Sevenless-1 (blue) participating in a cation-π interaction with Tyr884 of H-RAS (orange). The dihedral angle, CG-CD-NE-CZ, of Arg73 is 124.2 degrees. (PDB ID: 1BKD) Figure created using jV 3.212.

Mentions: The high prevalence of Arg at the hub interface provides a lot of binding flexibility to the hub. Arg forms multiple types of favourable interactions6. The Arg side chain is considerably flexible, forming a good anchor residue as a result of its ability to anchor its side chain into a binding groove of an interaction partner24. It also allows binding across interfaces in various orientations. The dihedral angle, CG-CD-NE-CZ, of Arg varies through a spectrum of values, from −120, −60, 60, 120, to 180 degrees, in the structures in our data set (Supplementary Table S4). For instance, a superposition of all structures of Ubiquitin with its various interaction partners binding the interface centered at Ile44, shows the various side-chain orientations for Arg42 which also participates in binding (Figures 5A, B). Along with salt bridges25 and hydrogen bonds16, Arg is also involved in cation-π interactions with aromatic residues16,26 across the interface. A cation-π interaction of Arg with Tyr in the hub, Son of Sevenless-1, is shown in Figure 5C. Arg also provides increased specificity of interaction16.


The role of charged surface residues in the binding ability of small hubs in protein-protein interaction networks
Selected views of Arginine participating in various types of interactions in different binding orientations. (A) Arg42 of Ubiquitin (blue) participating in a salt bridge with Asp444 of the CUE domain of Vacuolar protein sorting-associated protein VPS9 (orange). The dihedral angle, CG-CD-NE-CZ, of Arg42 is 131.9 degrees. (PDB ID: 1P3Q). (B) Arg42 of Ubiquitin (blue) forming a hydrogen bond with Gly47 backbone (distance 2.8 Å) of Tumor susceptibility gene 101 protein TSG101 (orange). The dihedral angle, CG-CD-NE-CZ, of Arg42 is −143.4 degrees. (PDB ID: 1S1Q). (C) Arg73 of Son Of Sevenless-1 (blue) participating in a cation-π interaction with Tyr884 of H-RAS (orange). The dihedral angle, CG-CD-NE-CZ, of Arg73 is 124.2 degrees. (PDB ID: 1BKD) Figure created using jV 3.212.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC5036656&req=5

f5-3_27: Selected views of Arginine participating in various types of interactions in different binding orientations. (A) Arg42 of Ubiquitin (blue) participating in a salt bridge with Asp444 of the CUE domain of Vacuolar protein sorting-associated protein VPS9 (orange). The dihedral angle, CG-CD-NE-CZ, of Arg42 is 131.9 degrees. (PDB ID: 1P3Q). (B) Arg42 of Ubiquitin (blue) forming a hydrogen bond with Gly47 backbone (distance 2.8 Å) of Tumor susceptibility gene 101 protein TSG101 (orange). The dihedral angle, CG-CD-NE-CZ, of Arg42 is −143.4 degrees. (PDB ID: 1S1Q). (C) Arg73 of Son Of Sevenless-1 (blue) participating in a cation-π interaction with Tyr884 of H-RAS (orange). The dihedral angle, CG-CD-NE-CZ, of Arg73 is 124.2 degrees. (PDB ID: 1BKD) Figure created using jV 3.212.
Mentions: The high prevalence of Arg at the hub interface provides a lot of binding flexibility to the hub. Arg forms multiple types of favourable interactions6. The Arg side chain is considerably flexible, forming a good anchor residue as a result of its ability to anchor its side chain into a binding groove of an interaction partner24. It also allows binding across interfaces in various orientations. The dihedral angle, CG-CD-NE-CZ, of Arg varies through a spectrum of values, from −120, −60, 60, 120, to 180 degrees, in the structures in our data set (Supplementary Table S4). For instance, a superposition of all structures of Ubiquitin with its various interaction partners binding the interface centered at Ile44, shows the various side-chain orientations for Arg42 which also participates in binding (Figures 5A, B). Along with salt bridges25 and hydrogen bonds16, Arg is also involved in cation-π interactions with aromatic residues16,26 across the interface. A cation-π interaction of Arg with Tyr in the hub, Son of Sevenless-1, is shown in Figure 5C. Arg also provides increased specificity of interaction16.

View Article: PubMed Central - PubMed

ABSTRACT

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.

No MeSH data available.


Related in: MedlinePlus