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Reconstructing the ubiquitin network: cross-talk with other systems and identification of novel functions.

Venancio TM, Balaji S, Iyer LM, Aravind L - Genome Biol. (2009)

Bottom Line: We devised two novel representations, the rank plot to understand the functional diversification of different components and the clique-specific point-wise mutual-information network to identify significant interactions in the Ub-system.We also identify novel components of SCF (Skp1-cullin-F-box)-dependent complexes, receptors in the ERAD (endoplasmic reticulum associated degradation) system and a key role for Sus1 in coordinating multiple Ub-related processes in chromatin dynamics.Combined with evolutionary information, the structure of this network helps in understanding the lineage-specific expansion of SCF complexes with a potential role in pathogen response and the origin of the ERAD and ESCRT systems.

View Article: PubMed Central - HTML - PubMed

Affiliation: National Center for Biotechnology Information, National Library of Medicine, NIH, Bethesda, MD 20894, USA. venancit@ncbi.nlm.nih.gov

ABSTRACT

Background: The ubiquitin system (Ub-system) can be defined as the ensemble of components including Ub/ubiquitin-like proteins, their conjugation and deconjugation apparatus, binding partners and the proteasomal system. While several studies have concentrated on structure-function relationships and evolution of individual components of the Ub-system, a study of the system as a whole is largely lacking.

Results: Using numerous genome-scale datasets, we assemble for the first time a comprehensive reconstruction of the budding yeast Ub-system, revealing static and dynamic properties. We devised two novel representations, the rank plot to understand the functional diversification of different components and the clique-specific point-wise mutual-information network to identify significant interactions in the Ub-system.

Conclusions: Using these representations, evidence is provided for the functional diversification of components such as SUMO-dependent Ub-ligases. We also identify novel components of SCF (Skp1-cullin-F-box)-dependent complexes, receptors in the ERAD (endoplasmic reticulum associated degradation) system and a key role for Sus1 in coordinating multiple Ub-related processes in chromatin dynamics. We present evidence for a major impact of the Ub-system on large parts of the proteome via its interaction with the transcription regulatory network. Furthermore, the dynamics of the Ub-network suggests that Ub and SUMO modifications might function cooperatively with transcription control in regulating cell-cycle-stage-specific complexes and in reinforcing periodicities in gene expression. Combined with evolutionary information, the structure of this network helps in understanding the lineage-specific expansion of SCF complexes with a potential role in pathogen response and the origin of the ERAD and ESCRT systems.

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U-net classes and their interactions. The graph represents the Ub pathway wherein individual nodes have been collapsed into their respective general protein classes. The different contributions of (a) protein-protein and (b) genetic interactions that contribute to the overall U-net are shown separately. The proteome represents the rest of the proteome (that is, minus the Ub-system). The U-net-spec connections are shown in green while those to the proteome are shown in mauve. The intra-proteasomal protein-protein interactions are seen to stand out in graph. The figure also implies that only a fraction of the modifications are reversed by the DUBs.
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Figure 2: U-net classes and their interactions. The graph represents the Ub pathway wherein individual nodes have been collapsed into their respective general protein classes. The different contributions of (a) protein-protein and (b) genetic interactions that contribute to the overall U-net are shown separately. The proteome represents the rest of the proteome (that is, minus the Ub-system). The U-net-spec connections are shown in green while those to the proteome are shown in mauve. The intra-proteasomal protein-protein interactions are seen to stand out in graph. The figure also implies that only a fraction of the modifications are reversed by the DUBs.

Mentions: The thus obtained U-net is an undirected graph, composed of 3,954 proteins (nodes) and 15,487 interactions (edges) representing genetic and protein-protein interactions of both covalent and non-covalent types (Figure 2; File S1 in Additional data file 1). Within the U-net a subnetwork can be identified, which is composed of all interactions between Ub-system components themselves, hereafter referred to as U-net-spec (for Ub specific network; Table S1 in Additional data file 1). In the U-net-spec the largest contribution is from protein-protein interactions of proteasome components (approximately 31.9% of U-net-spec interactions), which is reflective of the proteasome being a tightly interacting large protein complex (Figure 2a). In terms of connections to the rest of the proteome, there is a progression of increasing number of interactions in the order E1-E2-E3-Ub/Ubls (Figure 2a, b). This order is consistent with the observed biochemistry of the Ub-system, where there is increasing target specificity along the E1-E2-E3 enzyme cascade, with several E3s adding Ub/Ubls to more than one substrate [7]. As expected, Ub and SUMO are the two primary hubs (that is, highly connected nodes; Table S1 in Additional data file 1) in the network as they connect to a significant part of the proteome through direct covalent linkage. Other major hubs are the E2s Ubc7 and Rad6 (601 and 300 interactions, respectively), the E3 Rsp5 (376 connections) and the non-ATPase proteasomal subunit Rpn10 (432 connections) (all the information on connections and annotations are available in Table S1 in Additional data file 1).


Reconstructing the ubiquitin network: cross-talk with other systems and identification of novel functions.

Venancio TM, Balaji S, Iyer LM, Aravind L - Genome Biol. (2009)

U-net classes and their interactions. The graph represents the Ub pathway wherein individual nodes have been collapsed into their respective general protein classes. The different contributions of (a) protein-protein and (b) genetic interactions that contribute to the overall U-net are shown separately. The proteome represents the rest of the proteome (that is, minus the Ub-system). The U-net-spec connections are shown in green while those to the proteome are shown in mauve. The intra-proteasomal protein-protein interactions are seen to stand out in graph. The figure also implies that only a fraction of the modifications are reversed by the DUBs.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2691004&req=5

Figure 2: U-net classes and their interactions. The graph represents the Ub pathway wherein individual nodes have been collapsed into their respective general protein classes. The different contributions of (a) protein-protein and (b) genetic interactions that contribute to the overall U-net are shown separately. The proteome represents the rest of the proteome (that is, minus the Ub-system). The U-net-spec connections are shown in green while those to the proteome are shown in mauve. The intra-proteasomal protein-protein interactions are seen to stand out in graph. The figure also implies that only a fraction of the modifications are reversed by the DUBs.
Mentions: The thus obtained U-net is an undirected graph, composed of 3,954 proteins (nodes) and 15,487 interactions (edges) representing genetic and protein-protein interactions of both covalent and non-covalent types (Figure 2; File S1 in Additional data file 1). Within the U-net a subnetwork can be identified, which is composed of all interactions between Ub-system components themselves, hereafter referred to as U-net-spec (for Ub specific network; Table S1 in Additional data file 1). In the U-net-spec the largest contribution is from protein-protein interactions of proteasome components (approximately 31.9% of U-net-spec interactions), which is reflective of the proteasome being a tightly interacting large protein complex (Figure 2a). In terms of connections to the rest of the proteome, there is a progression of increasing number of interactions in the order E1-E2-E3-Ub/Ubls (Figure 2a, b). This order is consistent with the observed biochemistry of the Ub-system, where there is increasing target specificity along the E1-E2-E3 enzyme cascade, with several E3s adding Ub/Ubls to more than one substrate [7]. As expected, Ub and SUMO are the two primary hubs (that is, highly connected nodes; Table S1 in Additional data file 1) in the network as they connect to a significant part of the proteome through direct covalent linkage. Other major hubs are the E2s Ubc7 and Rad6 (601 and 300 interactions, respectively), the E3 Rsp5 (376 connections) and the non-ATPase proteasomal subunit Rpn10 (432 connections) (all the information on connections and annotations are available in Table S1 in Additional data file 1).

Bottom Line: We devised two novel representations, the rank plot to understand the functional diversification of different components and the clique-specific point-wise mutual-information network to identify significant interactions in the Ub-system.We also identify novel components of SCF (Skp1-cullin-F-box)-dependent complexes, receptors in the ERAD (endoplasmic reticulum associated degradation) system and a key role for Sus1 in coordinating multiple Ub-related processes in chromatin dynamics.Combined with evolutionary information, the structure of this network helps in understanding the lineage-specific expansion of SCF complexes with a potential role in pathogen response and the origin of the ERAD and ESCRT systems.

View Article: PubMed Central - HTML - PubMed

Affiliation: National Center for Biotechnology Information, National Library of Medicine, NIH, Bethesda, MD 20894, USA. venancit@ncbi.nlm.nih.gov

ABSTRACT

Background: The ubiquitin system (Ub-system) can be defined as the ensemble of components including Ub/ubiquitin-like proteins, their conjugation and deconjugation apparatus, binding partners and the proteasomal system. While several studies have concentrated on structure-function relationships and evolution of individual components of the Ub-system, a study of the system as a whole is largely lacking.

Results: Using numerous genome-scale datasets, we assemble for the first time a comprehensive reconstruction of the budding yeast Ub-system, revealing static and dynamic properties. We devised two novel representations, the rank plot to understand the functional diversification of different components and the clique-specific point-wise mutual-information network to identify significant interactions in the Ub-system.

Conclusions: Using these representations, evidence is provided for the functional diversification of components such as SUMO-dependent Ub-ligases. We also identify novel components of SCF (Skp1-cullin-F-box)-dependent complexes, receptors in the ERAD (endoplasmic reticulum associated degradation) system and a key role for Sus1 in coordinating multiple Ub-related processes in chromatin dynamics. We present evidence for a major impact of the Ub-system on large parts of the proteome via its interaction with the transcription regulatory network. Furthermore, the dynamics of the Ub-network suggests that Ub and SUMO modifications might function cooperatively with transcription control in regulating cell-cycle-stage-specific complexes and in reinforcing periodicities in gene expression. Combined with evolutionary information, the structure of this network helps in understanding the lineage-specific expansion of SCF complexes with a potential role in pathogen response and the origin of the ERAD and ESCRT systems.

Show MeSH