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Composite structural motifs of binding sites for delineating biological functions of proteins.

Kinjo AR, Nakamura H - PLoS ONE (2012)

Bottom Line: It is demonstrated that function similarity can be better inferred from composite motif similarity compared to the similarity of protein sequences or of individual binding sites.By integrating the composite motifs associated with each protein function, we define meta-composite motifs each of which is regarded as a time-independent diagrammatic representation of a biological process.The present results serve as a basis for bridging atomic structures to higher-order biological phenomena by classification and integration of binding site structures.

View Article: PubMed Central - PubMed

Affiliation: Institute for Protein Research, Osaka University, Suita, Osaka, Japan. akinjo@protein.osaka-u.ac.jp

ABSTRACT
Most biological processes are described as a series of interactions between proteins and other molecules, and interactions are in turn described in terms of atomic structures. To annotate protein functions as sets of interaction states at atomic resolution, and thereby to better understand the relation between protein interactions and biological functions, we conducted exhaustive all-against-all atomic structure comparisons of all known binding sites for ligands including small molecules, proteins and nucleic acids, and identified recurring elementary motifs. By integrating the elementary motifs associated with each subunit, we defined composite motifs that represent context-dependent combinations of elementary motifs. It is demonstrated that function similarity can be better inferred from composite motif similarity compared to the similarity of protein sequences or of individual binding sites. By integrating the composite motifs associated with each protein function, we define meta-composite motifs each of which is regarded as a time-independent diagrammatic representation of a biological process. It is shown that meta-composite motifs provide richer annotations of biological processes than sequence clusters. The present results serve as a basis for bridging atomic structures to higher-order biological phenomena by classification and integration of binding site structures.

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Examples of elementary and composite motifs.A: Concrete examples of elementary motifs (corresponding to B). Several binding sites belonging to each elementary motif are superimposed. The binding site atoms that constitute the elementary motif are shown in ball-and-stick representation with CPK coloring and ligands are shown in green wireframes (non-polymers) or tubes (proteins). These binding sites include subunits shown in C. Non-polymer ligands are phenylalanine and its analogs (N1), FAD (N2), and polyamines (N3). B: In this example, the combinations of 3 non-polymer binding elementary motifs (cyan triangles labeled N1, N2 and N3) and 3 protein binding elementary motif (orange rectangles labeled P1, P2 and P3) found in various protein subunits (black dots) define 3 distinct composite motifs (hexagons in magenta labeled C1, C2, and C3). Examples of each elementary motif are shown in molecular figures (A) right above the triangles or rectangles, and those of each composite motif are shown in molecular figures (C) right below the hexagons. Direct correspondence between elementary and composite motifs is indicated by thick edges in pale magenta. C: Concrete examples of composite motifs (corresponding to B). These 3 composite motifs share the same elementary motif for FAD binding (labeled N2 in B). Subunits (colored pink) containing the composite motifs (C1, C2, C3) are shown with elementary motifs in ball-and-stick representations (protein binding sites in orange, non-polymer binding sites in cyan) and with ligands in green (spacefill for non-polymers, cartoon for proteins). From left to right: L-amino acid oxidase (LAAO) from Calloselasma rhodostoma in homo-dimeric form (PDB ID: 1F8S [42], chain A); human lysine-specific histone demethylase 1 (KDM1) (PDB ID: 2IW5 [43], chain A); polyamine oxidase (PAO) from Zea mays in putative homo-dimeric form (PDB ID: 3KU9 [44], chain A, pdbx_struct_assembly.id 3). The protein figures were created using jV [75]. The network diagrams (also in Figs. 5 and 6) were created using Cytoscape [76].
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pone-0031437-g001: Examples of elementary and composite motifs.A: Concrete examples of elementary motifs (corresponding to B). Several binding sites belonging to each elementary motif are superimposed. The binding site atoms that constitute the elementary motif are shown in ball-and-stick representation with CPK coloring and ligands are shown in green wireframes (non-polymers) or tubes (proteins). These binding sites include subunits shown in C. Non-polymer ligands are phenylalanine and its analogs (N1), FAD (N2), and polyamines (N3). B: In this example, the combinations of 3 non-polymer binding elementary motifs (cyan triangles labeled N1, N2 and N3) and 3 protein binding elementary motif (orange rectangles labeled P1, P2 and P3) found in various protein subunits (black dots) define 3 distinct composite motifs (hexagons in magenta labeled C1, C2, and C3). Examples of each elementary motif are shown in molecular figures (A) right above the triangles or rectangles, and those of each composite motif are shown in molecular figures (C) right below the hexagons. Direct correspondence between elementary and composite motifs is indicated by thick edges in pale magenta. C: Concrete examples of composite motifs (corresponding to B). These 3 composite motifs share the same elementary motif for FAD binding (labeled N2 in B). Subunits (colored pink) containing the composite motifs (C1, C2, C3) are shown with elementary motifs in ball-and-stick representations (protein binding sites in orange, non-polymer binding sites in cyan) and with ligands in green (spacefill for non-polymers, cartoon for proteins). From left to right: L-amino acid oxidase (LAAO) from Calloselasma rhodostoma in homo-dimeric form (PDB ID: 1F8S [42], chain A); human lysine-specific histone demethylase 1 (KDM1) (PDB ID: 2IW5 [43], chain A); polyamine oxidase (PAO) from Zea mays in putative homo-dimeric form (PDB ID: 3KU9 [44], chain A, pdbx_struct_assembly.id 3). The protein figures were created using jV [75]. The network diagrams (also in Figs. 5 and 6) were created using Cytoscape [76].

Mentions: All-against-all structure comparisons of 410,254 non-polymer binding sites, 346,288 protein binding sites and 20,338 nucleic acid binding sites using the GIRAF structure search and alignment program [41] followed by complete linkage clustering yielded 5,869, 7,678 and 398 clusters (with at least 10 members) of non-polymer, protein and nucleic acid binding sites, respectively. (We did not use in the following analyses small clusters with less than 10 members because some small clusters exhibited spurious similarities.) We refer to these clusters as elementary motifs in the following. An elementary motif can be regarded as a bundle of mutually similar atomic dispositions of binding sites (Fig. 1A). It should be noted that the elementary motifs are solely based on the binding site structures, and they do not directly include the identity of the binding partners. We have previously performed comprehensive analyses of elementary motifs [14], [15]. It was found that most elementary motifs were confined within homologous families. In some exceptional cases, motifs were shared across non-homologous families with different folds, which included motifs for metal, mononucleotide or dinucleotide binding for non-polymer binding sites [14] and coiled-coil motifs for protein binding sites [15].


Composite structural motifs of binding sites for delineating biological functions of proteins.

Kinjo AR, Nakamura H - PLoS ONE (2012)

Examples of elementary and composite motifs.A: Concrete examples of elementary motifs (corresponding to B). Several binding sites belonging to each elementary motif are superimposed. The binding site atoms that constitute the elementary motif are shown in ball-and-stick representation with CPK coloring and ligands are shown in green wireframes (non-polymers) or tubes (proteins). These binding sites include subunits shown in C. Non-polymer ligands are phenylalanine and its analogs (N1), FAD (N2), and polyamines (N3). B: In this example, the combinations of 3 non-polymer binding elementary motifs (cyan triangles labeled N1, N2 and N3) and 3 protein binding elementary motif (orange rectangles labeled P1, P2 and P3) found in various protein subunits (black dots) define 3 distinct composite motifs (hexagons in magenta labeled C1, C2, and C3). Examples of each elementary motif are shown in molecular figures (A) right above the triangles or rectangles, and those of each composite motif are shown in molecular figures (C) right below the hexagons. Direct correspondence between elementary and composite motifs is indicated by thick edges in pale magenta. C: Concrete examples of composite motifs (corresponding to B). These 3 composite motifs share the same elementary motif for FAD binding (labeled N2 in B). Subunits (colored pink) containing the composite motifs (C1, C2, C3) are shown with elementary motifs in ball-and-stick representations (protein binding sites in orange, non-polymer binding sites in cyan) and with ligands in green (spacefill for non-polymers, cartoon for proteins). From left to right: L-amino acid oxidase (LAAO) from Calloselasma rhodostoma in homo-dimeric form (PDB ID: 1F8S [42], chain A); human lysine-specific histone demethylase 1 (KDM1) (PDB ID: 2IW5 [43], chain A); polyamine oxidase (PAO) from Zea mays in putative homo-dimeric form (PDB ID: 3KU9 [44], chain A, pdbx_struct_assembly.id 3). The protein figures were created using jV [75]. The network diagrams (also in Figs. 5 and 6) were created using Cytoscape [76].
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pone-0031437-g001: Examples of elementary and composite motifs.A: Concrete examples of elementary motifs (corresponding to B). Several binding sites belonging to each elementary motif are superimposed. The binding site atoms that constitute the elementary motif are shown in ball-and-stick representation with CPK coloring and ligands are shown in green wireframes (non-polymers) or tubes (proteins). These binding sites include subunits shown in C. Non-polymer ligands are phenylalanine and its analogs (N1), FAD (N2), and polyamines (N3). B: In this example, the combinations of 3 non-polymer binding elementary motifs (cyan triangles labeled N1, N2 and N3) and 3 protein binding elementary motif (orange rectangles labeled P1, P2 and P3) found in various protein subunits (black dots) define 3 distinct composite motifs (hexagons in magenta labeled C1, C2, and C3). Examples of each elementary motif are shown in molecular figures (A) right above the triangles or rectangles, and those of each composite motif are shown in molecular figures (C) right below the hexagons. Direct correspondence between elementary and composite motifs is indicated by thick edges in pale magenta. C: Concrete examples of composite motifs (corresponding to B). These 3 composite motifs share the same elementary motif for FAD binding (labeled N2 in B). Subunits (colored pink) containing the composite motifs (C1, C2, C3) are shown with elementary motifs in ball-and-stick representations (protein binding sites in orange, non-polymer binding sites in cyan) and with ligands in green (spacefill for non-polymers, cartoon for proteins). From left to right: L-amino acid oxidase (LAAO) from Calloselasma rhodostoma in homo-dimeric form (PDB ID: 1F8S [42], chain A); human lysine-specific histone demethylase 1 (KDM1) (PDB ID: 2IW5 [43], chain A); polyamine oxidase (PAO) from Zea mays in putative homo-dimeric form (PDB ID: 3KU9 [44], chain A, pdbx_struct_assembly.id 3). The protein figures were created using jV [75]. The network diagrams (also in Figs. 5 and 6) were created using Cytoscape [76].
Mentions: All-against-all structure comparisons of 410,254 non-polymer binding sites, 346,288 protein binding sites and 20,338 nucleic acid binding sites using the GIRAF structure search and alignment program [41] followed by complete linkage clustering yielded 5,869, 7,678 and 398 clusters (with at least 10 members) of non-polymer, protein and nucleic acid binding sites, respectively. (We did not use in the following analyses small clusters with less than 10 members because some small clusters exhibited spurious similarities.) We refer to these clusters as elementary motifs in the following. An elementary motif can be regarded as a bundle of mutually similar atomic dispositions of binding sites (Fig. 1A). It should be noted that the elementary motifs are solely based on the binding site structures, and they do not directly include the identity of the binding partners. We have previously performed comprehensive analyses of elementary motifs [14], [15]. It was found that most elementary motifs were confined within homologous families. In some exceptional cases, motifs were shared across non-homologous families with different folds, which included motifs for metal, mononucleotide or dinucleotide binding for non-polymer binding sites [14] and coiled-coil motifs for protein binding sites [15].

Bottom Line: It is demonstrated that function similarity can be better inferred from composite motif similarity compared to the similarity of protein sequences or of individual binding sites.By integrating the composite motifs associated with each protein function, we define meta-composite motifs each of which is regarded as a time-independent diagrammatic representation of a biological process.The present results serve as a basis for bridging atomic structures to higher-order biological phenomena by classification and integration of binding site structures.

View Article: PubMed Central - PubMed

Affiliation: Institute for Protein Research, Osaka University, Suita, Osaka, Japan. akinjo@protein.osaka-u.ac.jp

ABSTRACT
Most biological processes are described as a series of interactions between proteins and other molecules, and interactions are in turn described in terms of atomic structures. To annotate protein functions as sets of interaction states at atomic resolution, and thereby to better understand the relation between protein interactions and biological functions, we conducted exhaustive all-against-all atomic structure comparisons of all known binding sites for ligands including small molecules, proteins and nucleic acids, and identified recurring elementary motifs. By integrating the elementary motifs associated with each subunit, we defined composite motifs that represent context-dependent combinations of elementary motifs. It is demonstrated that function similarity can be better inferred from composite motif similarity compared to the similarity of protein sequences or of individual binding sites. By integrating the composite motifs associated with each protein function, we define meta-composite motifs each of which is regarded as a time-independent diagrammatic representation of a biological process. It is shown that meta-composite motifs provide richer annotations of biological processes than sequence clusters. The present results serve as a basis for bridging atomic structures to higher-order biological phenomena by classification and integration of binding site structures.

Show MeSH
Related in: MedlinePlus