Insights from the structural analysis of protein heterodimer interfaces

Sowmya, Gopichandran; Anita, Sathyanarayanan; Kangueane, Pandjassarame

doi:10.6026/97320630006137

Cited by 18 publications

(23 citation statements)

References 23 publications

(32 reference statements)

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“…The difference in percentages between interface polar residues and nonpolar residues (P% − NP%) gives the measure of the abundance of polar or nonpolar residues at the interface . The interface polarity abundance (P% − NP%) measure (described in Materials and Methods: Interface analysis) is significantly different among the different functional categories with P = 4.25E−05 (Table and Fig.…”

Section: Resultsmentioning

confidence: 99%

“…The classification of protein–protein complexes based on their composition, affinity, interface stability, and lifetime association into different groups has gained momentum in the past decade, although the boundaries between these classes is often indefinite, based on physiological conditions . Alternatively, the classification of complexes into major functional groups can be valuable in relating structural data to biological functions for better understanding of PPIs . Moreover, the classification of protein–protein complexes based on functions and their usefulness in improving prediction accuracy has been observed recently .…”

Section: Introductionmentioning

confidence: 99%

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Linking structural features of protein complexes and biological function

2015

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Protein-protein interaction (PPI) establishes the central basis for complex cellular networks in a biological cell. Association of proteins with other proteins occurs at varying affinities, yet with a high degree of specificity. PPIs lead to diverse functionality such as catalysis, regulation, signaling, immunity, and inhibition, playing a crucial role in functional genomics. The molecular principle of such interactions is often elusive in nature. Therefore, a comprehensive analysis of known protein complexes from the Protein Data Bank (PDB) is essential for the characterization of structural interface features to determine structure-function relationship. Thus, we analyzed a nonredundant dataset of 278 heterodimer protein complexes, categorized into major functional classes, for distinguishing features. Interestingly, our analysis has identified five key features (interface area, interface polar residue abundance, hydrogen bonds, solvation free energy gain from interface formation, and binding energy) that are discriminatory among the functional classes using Kruskal-Wallis rank sum test. Significant correlations between these PPI interface features amongst functional categories are also documented. Salt bridges correlate with interface area in regulator-inhibitors (r 5 0.75). These representative features have implications for the prediction of potential function of novel protein complexes. The results provide molecular insights for better understanding of PPIs and their relation to biological functions.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Linking structural features of protein complexes and biological function

2015

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“…It consists of 40 Enzymes, 144 Regulatory, 25 Enzyme inhibitors, 27 Regulatory inhibitors, 18 Immune complexes and 24 biological assembly complexes (Figure 1). This dataset is similar to a manually curated dataset having functional annotations described earlier by Sowmya et al (2011) [21]. We further grouped complexes associated with regulator, enzyme and biological assemblies as obligatory (essential) and those of enzyme and regulatory inhibitors as nonobligatory (unwanted).…”

Section: Methodsmentioning

confidence: 99%

“…The correlation of determination r2 was calculated for energy and interface size among class A (interface non-polar residues is more than surface) and class B (interface non-polar residues less than surface) [21]. …”

Section: Tablementioning

confidence: 99%

Protein-protein interfaces are vdW dominant with selective H-bonds and (or) electrostatics towards broad functional specificity

et al. 2017

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Several catalysis, cellular regulation, immune function, cell wall assembly, transport, signaling and inhibition occur through Protein- Protein Interactions (PPI). This is possible with the formation of specific yet stable protein-protein interfaces. Therefore, it is of interest to understand its molecular principles using structural data in relation to known function. Several interface features have been documented using known X-ray structures of protein complexes since 1975. This has improved our understanding of the interface using structural features such as interface area, binding energy, hydrophobicity, relative hydrophobicity, salt bridges and hydrogen bonds. The strength of binding between two proteins is dependent on interface size (number of residues at the interface) and thus its corresponding interface area. It is known that large interfaces have high binding energy (sum of (van der Waals) vdW, H-bonds, electrostatics). However, the selective role played by each of these energy components and more especially that of vdW is not explicitly known. Therefore, it is important to document their individual role in known protein-protein structural complexes. It is of interest to relate interface size with vdW, H-bonds and electrostatic interactions at the interfaces of protein structural complexes with known function using statistical and multiple linear regression analysis methods to identify the prominent force. We used the manually curated non-redundant dataset of 278 hetero-dimeric protein structural complexes grouped using known functions by Sowmya et al. (2015) to gain additional insight to this phenomenon using a robust inter-atomic non-covalent interaction analyzing tool PPCheck (Anshul and Sowdhamini, 2015). This dataset consists of obligatory (enzymes, regulator, biological assembly), immune and nonobligatory (enzyme and regulator inhibitors) complexes. Results show that the total binding energy is more for large interfaces. However, this is not true for its individual energy factors. Analysis shows that vdW energies contribute to about 75% ± 11% on average among all complexes and it also increases with interface size (r2 ranging from 0.67 to 0.89 with p<0.01) at 95% confidence limit irrespective of molecular function. Thus, vdW is both dominant and proportional at the interface independent of molecular function. Nevertheless, H bond energy contributes to 15% ± 6.5% on average in these complexes. It also moderately increases with interface size (r2 ranging from 0.43 to 0.61 with p<0.01) only among obligatory and immune complexes. Moreover, there is about 11.3% ± 8.7% contribution by electrostatic energy. It increases with interface size specifically among non-obligatory regulator-inhibitors (r2 = 0.44). It is implied that both H-bonds and electrostatics are neither dominant nor proportional at the interface. Nonetheless, their presence cannot be ignored in binding. Therefore, H-bonds and (or) electrostatic energy having specific role for improved stability in complexes is implied. Thus, vdW is commo...

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“…12 entries with N-to C-termini distances of less than 15 Å were identified ( Supplementary Table S2). This protocol of identifying PDB entries with heterodimeric proteins is similar to that of Sowmya et al (2011).…”

Section: Heterodimer Selectionmentioning

confidence: 99%

Protein design by fusion: implications for protein structure prediction and evolution

Skorupka

Han

Nam

et al. 2013

Acta Crystallogr D Biol Cryst

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Domain fusion is a useful tool in protein design. Here, the structure of a fusion of the heterodimeric flagella-assembly proteins FliS and FliC is reported. Although the ability of the fusion protein to maintain the structure of the heterodimer may be apparent, threading-based structural predictions do not properly fuse the heterodimer. Additional examples of naturally occurring heterodimers that are homologous to full-length proteins were identified. These examples highlight that the designed protein was engineered by the same tools as used in the natural evolution of proteins and that heterodimeric structures contain a wealth of information, currently unused, that can improve structural predictions.

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Insights from the structural analysis of protein heterodimer interfaces

Cited by 18 publications

References 23 publications

Linking structural features of protein complexes and biological function

Linking structural features of protein complexes and biological function

Protein-protein interfaces are vdW dominant with selective H-bonds and (or) electrostatics towards broad functional specificity

Protein design by fusion: implications for protein structure prediction and evolution

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