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      Systems analysis of the genetic interaction network of yeast molecular chaperones

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          Abstract

          Many molecular chaperones were found to be central drivers of the yeast whole genome genetic interaction network topology.

          Abstract

          Molecular chaperones are typically promiscuous interacting proteins that function globally in the cell to maintain protein homeostasis. Recently, we had carried out experiments that elucidated a comprehensive interaction network for the core 67 chaperones and 15 cochaperones in the budding yeast Saccharomyces cerevisiae [Rizzolo et al., Cell Rep., 2017, 20, 2735–2748]. Here, the genetic ( i.e. epistatic) interaction network obtained for chaperones was further analyzed, revealing that the global topological parameters of the resulting network have a more central role in mediating interactions in comparison to the rest of the proteins in the cell. Most notably, we observed Hsp10, Hsp70 Ssz1 chaperone, and Hsp90 cochaperone Cdc37 to be the main drivers of the network architecture. Systematic analysis on the physicochemical properties for all chaperone interactors further revealed the presence of preferential domains and folds that are highly interactive with chaperones such as the WD40 repeat domain. Further analysis with established cellular complexes revealed the involvement of R2TP chaperone in quaternary structure formation. Our results thus provide a global overview of the chaperone network properties in yeast, expanding our understanding of their functional diversity and their role in protein homeostasis.

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          Most cited references23

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          Lethality and centrality in protein networks

          In this paper we present the first mathematical analysis of the protein interaction network found in the yeast, S. cerevisiae. We show that, (a) the identified protein network display a characteristic scale-free topology that demonstrate striking similarity to the inherent organization of metabolic networks in particular, and to that of robust and error-tolerant networks in general. (b) the likelihood that deletion of an individual gene product will prove lethal for the yeast cell clearly correlates with the number of interactions the protein has, meaning that highly-connected proteins are more likely to prove essential than proteins with low number of links to other proteins. These results suggest that a scale-free architecture is a generic property of cellular networks attributable to universal self-organizing principles of robust and error-tolerant networks and that will likely to represent a generic topology for protein-protein interactions.
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            Is Open Access

            Hierarchical organization of modularity in metabolic networks

            Spatially or chemically isolated functional modules composed of several cellular components and carrying discrete functions are considered fundamental building blocks of cellular organization, but their presence in highly integrated biochemical networks lacks quantitative support. Here we show that the metabolic networks of 43 distinct organisms are organized into many small, highly connected topologic modules that combine in a hierarchical manner into larger, less cohesive units, their number and degree of clustering following a power law. Within Escherichia coli the uncovered hierarchical modularity closely overlaps with known metabolic functions. The identified network architecture may be generic to system-level cellular organization.
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              A global genetic interaction network maps a wiring diagram of cellular function.

              We generated a global genetic interaction network for Saccharomyces cerevisiae, constructing more than 23 million double mutants, identifying about 550,000 negative and about 350,000 positive genetic interactions. This comprehensive network maps genetic interactions for essential gene pairs, highlighting essential genes as densely connected hubs. Genetic interaction profiles enabled assembly of a hierarchical model of cell function, including modules corresponding to protein complexes and pathways, biological processes, and cellular compartments. Negative interactions connected functionally related genes, mapped core bioprocesses, and identified pleiotropic genes, whereas positive interactions often mapped general regulatory connections among gene pairs, rather than shared functionality. The global network illustrates how coherent sets of genetic interactions connect protein complex and pathway modules to map a functional wiring diagram of the cell.
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                Author and article information

                Journal
                MOOMAW
                Molecular Omics
                Mol. Omics
                Royal Society of Chemistry (RSC)
                2515-4184
                2018
                2018
                : 14
                : 2
                : 82-94
                Affiliations
                [1 ]Department of Biochemistry
                [2 ]University of Toronto
                [3 ]Toronto
                [4 ]Canada
                [5 ]Department of Computer Science
                [6 ]University of Regina
                [7 ]Regina
                [8 ]Research and Innovation Centre
                [9 ]The Donnelly Centre
                [10 ]Department of Chemistry
                Article
                10.1039/C7MO00142H
                29659649
                bfd4ca98-b80a-4a7f-a4fa-78f115655ab2
                © 2018

                http://rsc.li/journals-terms-of-use

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