Identification of Key Residues in Proteins Through Centrality Analysis and Flexibility Prediction with RINspector

Brysbaert, Guillaume; Mauri, Théo; Ruyck, Jérôme de; Lensink, Marc F.

doi:10.1002/cpbi.66

Cited by 15 publications

(14 citation statements)

References 20 publications

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“…Recently, a network analysis based on graph theory, which is popular in social sciences and complex-system studies, has been applied to a protein structure to elucidate structurally and functionally important residues, intra-and interprotein communication, and allostery [23][24][25][26][27][28][29][30]. The network analysis is considered to be effective for revealing the communication between remote residues via other residues in the protein.…”

Section: Betweennessmentioning

confidence: 99%

“…A residue was treated as the node, and the edge was defined as a link between two residues that made contact with each other and moved coherently in a specific normal mode. A residue centrality in the network such as closeness and betweenness is generally used to predict important residues for transmitting information across a protein structure [23][24][25][26][27][28][29][30]. We paid special attention to two residues with high betweenness linked in the dynamic PSN and located on different subunits.…”

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confidence: 99%

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Dynamic properties of oligomers that characterize low-frequency normal modes

Wako

Endo

2019

BIOPHYSICS

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Dynamics of oligomeric proteins (one trimer, two tetramers, and one hexamer) were studied by elastic network model-based normal mode analysis to characterize their large-scale concerted motions. First, the oligomer motions were simplified by considering rigid-body motions of individual subunits. The subunit motions were resolved into three components in a cylindrical coordinate system: radial, tangential, and axial ones. Single component is dominant in certain normal modes. However, more than one component is mixed in others. The subunits move symmetrically in certain normal modes and as a standing wave with several wave nodes in others. Secondly, special attention was paid to atoms on inter-subunit interfaces. Their displacement vectors were decomposed into intrasubunit deformative (internal) and rigid-body (external) motions in individual subunits. The fact that most of the cosines of the internal and external motion vectors were negative for the atoms on the inter-subunit interfaces, indicated their opposing movements. Finally, a structural network of residues defined for each normal mode was investigated; the network was constructed by connecting two residues in contact and moving coherently. The centrality measure "betweenness" of each residue was calculated for the networks. Several residues with significantly high betweenness were observed on the inter-subunit interfaces. The results indicate that these residues are responsible for oligomer dynamics. It was also observed that amino acid residues with significantly high betweenness were more conservative. This supports that the betweenness is an effective characteristic for identifying an important residue in protein dynamics.Key words: betweenness, degeneracy of normal modes, conservation of amino acid residues, protein structure network, cylindrical coordinate system Most proteins function in an oligomeric form [1]. An advantage of oligomers over monomers is that the oligomeric form permits proteins to initiate allostery and cooperativity in achieving their function. Studies on the dynamics of oligomers can provide key information that reveals the mechanism of the allostery and cooperativity. Molecular dynamics (MD) simulation and normal mode analysis (NMA) can be effective theoretical methods to address this problem [2-9]. Although they can generate a large amount of data regarding protein motions at the atomic level and the motions Dynamics of oligomeric proteins were studied by elastic network model-based normal mode analysis to characterize their large-scale concerted motions. (1) The rigid-body motions of individual subunits were characterized by the radial, tangential, and axial components in a cylindrical coordinate system. (2) The motions of atoms on the intersubunit interfaces were characterized by the opposing motions of intra-subunit deformation and rigid-body motion of the subunit. (3) A dynamic protein structure network was defined in each mode, and the centrality measure, betweenness, was calculated for each residue. The results indicate tha...

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Section: Betweennessmentioning

confidence: 99%

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confidence: 99%

Dynamic properties of oligomers that characterize low-frequency normal modes

Wako

Endo

2019

BIOPHYSICS

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“…The average shortest path length (ASPL) is the average of shortest path lengths of all possible pairs of nodes in a network. In the residue centrality analysis, a per-node Z -score is calculated as follows:zk=∆Lk−true∆bold-italicL¯σ where ∆Lk is the change of the ASPL under removal of node k, true∆bold-italicL¯ is the change of the ASPL under node removal averaged over all protein residues and σ is the corresponding standard deviation.We considered those nodes that exhibited a value ≥ 2 as central (for more details, see [25,49]). For comparison to the binding modes identified in [3], we focused on central residues at the interface between the two chains.…”

Section: Figure A1mentioning

confidence: 99%

“…We considered those nodes that exhibited a value ≥ 2 as central (for more details, see [25,49]). For comparison to the binding modes identified in [3], we focused on central residues at the interface between the two chains.…”

Section: Figure A1mentioning

confidence: 99%

Identification of Novel Interaction Partners of Ets-1: Focus on DNA Repair

Brysbaert

Ruyck

Aumercier

et al. 2019

Genes

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The transcription factor Ets-1 (ETS proto-oncogene 1) shows low expression levels except in specific biological processes like haematopoiesis or angiogenesis. Elevated levels of expression are observed in tumor progression, resulting in Ets-1 being named an oncoprotein. It has recently been shown that Ets-1 interacts with two DNA repair enzymes, PARP-1 (poly(ADP-ribose) polymerase 1) and DNA-PK (DNA-dependent protein kinase), through two different domains and that these interactions play a role in cancer. Considering that Ets-1 can bind to distinctly different domains of two DNA repair enzymes, we hypothesized that the interaction can be transposed onto homologs of the respective domains. We have searched for sequence and structure homologs of the interacting ETS(Ets-1), BRCT(PARP-1) and SAP(DNA-PK) domains, and have identified several candidate binding pairs that are currently not annotated as such. Many of the Ets-1 partners are associated to DNA repair mechanisms. We have applied protein-protein docking to establish putative interaction poses and investigated these using centrality analyses at the protein residue level. Most of the identified poses are virtually similar to our recently established interaction model for Ets-1/PARP-1 and Ets-1/DNA-PK. Our work illustrates the potentially high number of interactors of Ets-1, in particular involved in DNA repair mechanisms, which shows the oncoprotein as a potential important regulator of the mechanism.

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“…In order to better understand the role played by each residue in shaping protein function, it is proper to consider the protein structure as a network of amino acids that interact with each other in the three-dimensional space via various chemical interactions. In the past few years, network formalism has been a popular approach for studying individual proteins as well as protein complexes with the aim of understanding the underlying structural organization within the protein structure and elucidating the importance and functional roles of individual residues (18–23). In this approach, a Protein Structure Network (PSN) is constructed by taking residues within the structure as nodes and adding edges between them using distance cutoffs or other more advanced criteria.…”

Section: Introductionmentioning

confidence: 99%

ProSNEx: a web-based application for exploration and analysis of protein structures using network formalism

Aydinkal

Serçinoğlu

Ozbek

2019

Nucleic Acids Research

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ProSNEx (Protein Structure Network Explorer) is a web service for construction and analysis of Protein Structure Networks (PSNs) alongside amino acid flexibility, sequence conservation and annotation features. ProSNEx constructs a PSN by adding nodes to represent residues and edges between these nodes using user-specified interaction distance cutoffs for either carbon-alpha, carbon-beta or atom-pair contact networks. Different types of weighted networks can also be constructed by using either (i) the residue-residue interaction energies in the format returned by gRINN, resulting in a Protein Energy Network (PEN); (ii) the dynamical cross correlations from a coarse-grained Normal Mode Analysis (NMA) of the protein structure; (iii) interaction strength. Upon construction of the network, common network metrics (such as node centralities) as well as shortest paths between nodes and k-cliques are calculated. Moreover, additional features of each residue in the form of conservation scores and mutation/natural variant information are included in the analysis. By this way, tool offers an enhanced and direct comparison of network-based residue metrics with other types of biological information. ProSNEx is free and open to all users without login requirement at http://prosnex-tool.com.

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Identification of Key Residues in Proteins Through Centrality Analysis and Flexibility Prediction with RINspector

Cited by 15 publications

References 20 publications

Dynamic properties of oligomers that characterize low-frequency normal modes

Dynamic properties of oligomers that characterize low-frequency normal modes

Identification of Novel Interaction Partners of Ets-1: Focus on DNA Repair

ProSNEx: a web-based application for exploration and analysis of protein structures using network formalism

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