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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.


Binding interfaces of hubs and non-hubs. (A) Ubiquitin (PDB ID: 1WR1-A) (B) Surface potential of Ubiquitin (1wr1_1-A from eF-site12). (C) Ubiquitin (pink) bound to two molecules of Rabex5 (light blue) using distinct binding interfaces shown in blue (Lys6, Thr7, Gly10, Arg42, Ile44, Ala46, Gly47, His68, Val70) and purple (Ser20, Glu51, Arg54, Thr55, Ser57, Asp58, Tyr59, Asn60, Gln62), respectively (PDB ID: 2C7N). (D) Ferredoxin (PDB ID: 1GAQ-B) (E) Surface potential of Ferredoxin (1gaq-B from eF-site12). (F) Ferredoxin (pink) bound to Ferredoxin NADP+ reductase (FNR) (light blue) using the interface residues shown in blue (Gln61, Leu64, Asp65, Asp66, Gln68, Leu95, Thr96, Gly97, Ala98). Purple residues (Glu29, Glu30, Asp34, Glu92, Glu93, Glu94) show the binding site of Ferredoxin to Sulphite reductase (SiR) (PDB ID: 1GAQ). Red indicates negative potential, blue indicates positive potential and yellow indicates hydropathy in B and E. Figure created using jV 3.212.
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f4-3_27: Binding interfaces of hubs and non-hubs. (A) Ubiquitin (PDB ID: 1WR1-A) (B) Surface potential of Ubiquitin (1wr1_1-A from eF-site12). (C) Ubiquitin (pink) bound to two molecules of Rabex5 (light blue) using distinct binding interfaces shown in blue (Lys6, Thr7, Gly10, Arg42, Ile44, Ala46, Gly47, His68, Val70) and purple (Ser20, Glu51, Arg54, Thr55, Ser57, Asp58, Tyr59, Asn60, Gln62), respectively (PDB ID: 2C7N). (D) Ferredoxin (PDB ID: 1GAQ-B) (E) Surface potential of Ferredoxin (1gaq-B from eF-site12). (F) Ferredoxin (pink) bound to Ferredoxin NADP+ reductase (FNR) (light blue) using the interface residues shown in blue (Gln61, Leu64, Asp65, Asp66, Gln68, Leu95, Thr96, Gly97, Ala98). Purple residues (Glu29, Glu30, Asp34, Glu92, Glu93, Glu94) show the binding site of Ferredoxin to Sulphite reductase (SiR) (PDB ID: 1GAQ). Red indicates negative potential, blue indicates positive potential and yellow indicates hydropathy in B and E. Figure created using jV 3.212.

Mentions: Using multipole expansion, we find that the charges are widely distributed over the surfaces of hubs. The residue enrichment results clearly imply that more charged residues are present on the exposed surfaces of hubs as compared to the interfaces. This indicates that charged residues on hub surfaces contribute to the promiscuity of hubs while primarily acting from the exposed surface. Clearly, this does not mean that hubs do not use multiple interfaces to bind their targets. But the results indicate that irrespective of the number of interfaces used, the charged residues, except Arg, are more likely to be found on the exposed surface than at the interface. For instance, in our dataset some hubs do have more than one interface, but generally do not have a very large number of interfaces spread across their surfaces. Figure 4 shows two such hubs, Ubiquitin and Ferredoxin, that have two binding sites each, using which they bind their known partners. Until recently, Ubiquitin was known to have only one binding site that it uses to bind its targets. This site is primarily hydrophobic and centered around Ile44. Several proteins were known to bind this interface somewhat differently with varying weak binding affinities17. A new site has now been found using which Ubiquitin binds Rabex5. This interface is slightly charged and centered around Asp5818. In the case of Ferredoxin, two highly charged binding sites are used to interact with Ferredoxin-NADP+ reductase and sulfite reductase, respectively19.


The role of charged surface residues in the binding ability of small hubs in protein-protein interaction networks
Binding interfaces of hubs and non-hubs. (A) Ubiquitin (PDB ID: 1WR1-A) (B) Surface potential of Ubiquitin (1wr1_1-A from eF-site12). (C) Ubiquitin (pink) bound to two molecules of Rabex5 (light blue) using distinct binding interfaces shown in blue (Lys6, Thr7, Gly10, Arg42, Ile44, Ala46, Gly47, His68, Val70) and purple (Ser20, Glu51, Arg54, Thr55, Ser57, Asp58, Tyr59, Asn60, Gln62), respectively (PDB ID: 2C7N). (D) Ferredoxin (PDB ID: 1GAQ-B) (E) Surface potential of Ferredoxin (1gaq-B from eF-site12). (F) Ferredoxin (pink) bound to Ferredoxin NADP+ reductase (FNR) (light blue) using the interface residues shown in blue (Gln61, Leu64, Asp65, Asp66, Gln68, Leu95, Thr96, Gly97, Ala98). Purple residues (Glu29, Glu30, Asp34, Glu92, Glu93, Glu94) show the binding site of Ferredoxin to Sulphite reductase (SiR) (PDB ID: 1GAQ). Red indicates negative potential, blue indicates positive potential and yellow indicates hydropathy in B and E. Figure created using jV 3.212.
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f4-3_27: Binding interfaces of hubs and non-hubs. (A) Ubiquitin (PDB ID: 1WR1-A) (B) Surface potential of Ubiquitin (1wr1_1-A from eF-site12). (C) Ubiquitin (pink) bound to two molecules of Rabex5 (light blue) using distinct binding interfaces shown in blue (Lys6, Thr7, Gly10, Arg42, Ile44, Ala46, Gly47, His68, Val70) and purple (Ser20, Glu51, Arg54, Thr55, Ser57, Asp58, Tyr59, Asn60, Gln62), respectively (PDB ID: 2C7N). (D) Ferredoxin (PDB ID: 1GAQ-B) (E) Surface potential of Ferredoxin (1gaq-B from eF-site12). (F) Ferredoxin (pink) bound to Ferredoxin NADP+ reductase (FNR) (light blue) using the interface residues shown in blue (Gln61, Leu64, Asp65, Asp66, Gln68, Leu95, Thr96, Gly97, Ala98). Purple residues (Glu29, Glu30, Asp34, Glu92, Glu93, Glu94) show the binding site of Ferredoxin to Sulphite reductase (SiR) (PDB ID: 1GAQ). Red indicates negative potential, blue indicates positive potential and yellow indicates hydropathy in B and E. Figure created using jV 3.212.
Mentions: Using multipole expansion, we find that the charges are widely distributed over the surfaces of hubs. The residue enrichment results clearly imply that more charged residues are present on the exposed surfaces of hubs as compared to the interfaces. This indicates that charged residues on hub surfaces contribute to the promiscuity of hubs while primarily acting from the exposed surface. Clearly, this does not mean that hubs do not use multiple interfaces to bind their targets. But the results indicate that irrespective of the number of interfaces used, the charged residues, except Arg, are more likely to be found on the exposed surface than at the interface. For instance, in our dataset some hubs do have more than one interface, but generally do not have a very large number of interfaces spread across their surfaces. Figure 4 shows two such hubs, Ubiquitin and Ferredoxin, that have two binding sites each, using which they bind their known partners. Until recently, Ubiquitin was known to have only one binding site that it uses to bind its targets. This site is primarily hydrophobic and centered around Ile44. Several proteins were known to bind this interface somewhat differently with varying weak binding affinities17. A new site has now been found using which Ubiquitin binds Rabex5. This interface is slightly charged and centered around Asp5818. In the case of Ferredoxin, two highly charged binding sites are used to interact with Ferredoxin-NADP+ reductase and sulfite reductase, respectively19.

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.