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

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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.


Relative enrichment of conserved interface (black) and exposed surface (white) residues in (A) hubs and (B) non-hubs.
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f3-3_27: Relative enrichment of conserved interface (black) and exposed surface (white) residues in (A) hubs and (B) non-hubs.

Mentions: In order to determine if the charged residues on hub surfaces act, primarily, through multiple interfaces or through the exposed surface (non-interface), we studied the enrichment of conserved interface and exposed surface residues in hubs with respect to its total residue propensity. We looked for the conserved residues on the surface because we wanted to identify those that were important to protein function. We were able to identify conserved interface and exposed surface residues for 31 hubs and 20 non-hubs (Supplementary Tables S1 and S2). Table 1 and Figure 3 give the enrichment of the conserved residues at the interface and exposed surface of hubs and non-hubs. We also checked the correlation of the enrichment of conserved interface residues in all 51 proteins (31 hubs and 20 non-hubs) with the interface hotspots identified by Bogan and Thorn6. Our data correlates reasonably well with the experimentally determined hotspots at r=0.60 (t=5.27, p=0.001), when the outlier, Trp, is removed (Supplementary Table S3). The correlation coefficients for 31 hubs and 20 non-hubs with the interface hotspot data, independently, are 0.60 and 0.30 respectively.


The role of charged surface residues in the binding ability of small hubs in protein-protein interaction networks
Relative enrichment of conserved interface (black) and exposed surface (white) residues in (A) hubs and (B) non-hubs.
© Copyright Policy
Related In: Results  -  Collection

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

f3-3_27: Relative enrichment of conserved interface (black) and exposed surface (white) residues in (A) hubs and (B) non-hubs.
Mentions: In order to determine if the charged residues on hub surfaces act, primarily, through multiple interfaces or through the exposed surface (non-interface), we studied the enrichment of conserved interface and exposed surface residues in hubs with respect to its total residue propensity. We looked for the conserved residues on the surface because we wanted to identify those that were important to protein function. We were able to identify conserved interface and exposed surface residues for 31 hubs and 20 non-hubs (Supplementary Tables S1 and S2). Table 1 and Figure 3 give the enrichment of the conserved residues at the interface and exposed surface of hubs and non-hubs. We also checked the correlation of the enrichment of conserved interface residues in all 51 proteins (31 hubs and 20 non-hubs) with the interface hotspots identified by Bogan and Thorn6. Our data correlates reasonably well with the experimentally determined hotspots at r=0.60 (t=5.27, p=0.001), when the outlier, Trp, is removed (Supplementary Table S3). The correlation coefficients for 31 hubs and 20 non-hubs with the interface hotspot data, independently, are 0.60 and 0.30 respectively.

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.