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.


Percentage of hubs and non-hubs with a dominant dipole (green), quadrupole (blue) or octupole (orange) moment.
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC5036656&req=5

f2-3_27: Percentage of hubs and non-hubs with a dominant dipole (green), quadrupole (blue) or octupole (orange) moment.

Mentions: Figure 2 shows the percentage of 50 hubs and 131 non-hubs with a dominant dipole, quadrupole and octupole moments. The combination of quadrupole and octupole moments is dominant in 64% of hubs and 63% non-hubs. Thus, on average, small hubs and non-hubs show a dominant quadrupolar or octupolar nature in their surface charge distribution. However, we do not find any significant difference in the distribution of charges on the surfaces of hubs and non-hubs. A comparison of the monopole moments of hubs and non-hubs shows that 51.43% hubs have a positive monopole moment as compared to 40.74% non-hubs, indicating a net positive charge on the hub surface. The dominance of quadrupolar or octupolar moments in hubs can be interpreted by understanding the physical manifestation of each moment in the multipole expansion. The monopole moment corresponds to the net charge on the surface of the protein while the dipole moment corresponds to the average position of the positive and negative charges along each co-ordinate axis. The quadrupole and octupole moments represent the spread of charge from the co-ordinate axes. Thus a dominant quadrupolar or octupolar nature corresponds to a greater spread of charge over the surface of the sphere, and hence the surface of the protein. This suggests that the charged residues on the surfaces of hubs are well distributed over the surface. Since the surface charges are implicated in promiscuous binding of hubs1 and they are spread out over the surface, it leads to two possible roles for the charged residues: (i) the charged residues act directly through short-range electrostatic interactions with the residues of the partner proteins through several different interfaces distributed over the surface of the hub to bind multiple partners, or (ii) the charged surface residues participate in long-range electrostatic interactions, from the exposed surface, with the residues of the partner proteins in the form of electrostatic steering4, while using only a few specific interfaces for binding. In the following sections, we examine which of these roles is predominantly observed in small hubs.


The role of charged surface residues in the binding ability of small hubs in protein-protein interaction networks
Percentage of hubs and non-hubs with a dominant dipole (green), quadrupole (blue) or octupole (orange) moment.
© Copyright Policy
Related In: Results  -  Collection

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

f2-3_27: Percentage of hubs and non-hubs with a dominant dipole (green), quadrupole (blue) or octupole (orange) moment.
Mentions: Figure 2 shows the percentage of 50 hubs and 131 non-hubs with a dominant dipole, quadrupole and octupole moments. The combination of quadrupole and octupole moments is dominant in 64% of hubs and 63% non-hubs. Thus, on average, small hubs and non-hubs show a dominant quadrupolar or octupolar nature in their surface charge distribution. However, we do not find any significant difference in the distribution of charges on the surfaces of hubs and non-hubs. A comparison of the monopole moments of hubs and non-hubs shows that 51.43% hubs have a positive monopole moment as compared to 40.74% non-hubs, indicating a net positive charge on the hub surface. The dominance of quadrupolar or octupolar moments in hubs can be interpreted by understanding the physical manifestation of each moment in the multipole expansion. The monopole moment corresponds to the net charge on the surface of the protein while the dipole moment corresponds to the average position of the positive and negative charges along each co-ordinate axis. The quadrupole and octupole moments represent the spread of charge from the co-ordinate axes. Thus a dominant quadrupolar or octupolar nature corresponds to a greater spread of charge over the surface of the sphere, and hence the surface of the protein. This suggests that the charged residues on the surfaces of hubs are well distributed over the surface. Since the surface charges are implicated in promiscuous binding of hubs1 and they are spread out over the surface, it leads to two possible roles for the charged residues: (i) the charged residues act directly through short-range electrostatic interactions with the residues of the partner proteins through several different interfaces distributed over the surface of the hub to bind multiple partners, or (ii) the charged surface residues participate in long-range electrostatic interactions, from the exposed surface, with the residues of the partner proteins in the form of electrostatic steering4, while using only a few specific interfaces for binding. In the following sections, we examine which of these roles is predominantly observed in small hubs.

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.