Computed structures of core eukaryotic protein complexes.
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ABSTRACT:
SUBMITTER: Humphreys IR
PROVIDER: S-EPMC7612107 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Many cellular functions involve protein complexes that are formed by multiple interacting proteins. Tandem Affinity Purification (TAP) is a popular experimental method for detecting such multi-protein interactions. However, current computational methods that predict protein complexes from TAP data require converting the co-complex relationships in TAP data into binary interactions. The resulting pairwise protein-protein interaction (PPI) network is then mined for densely connected regions that are identified as putative protein complexes. Converting the TAP data into PPI data not only introduces errors but also loses useful information about the underlying multi-protein relationships that can be exploited to detect the internal organization (i.e., core-attachment structures) of protein complexes. In this article, we propose a method called CACHET that detects protein complexes with Core-AttaCHment structures directly from bipartitETAP data. CACHET models the TAP data as a bipartite graph in which the two vertex sets are the baits and the preys, respectively. The edges between the two vertex sets represent bait-prey relationships. CACHET first focuses on detecting high-quality protein-complex cores from the bipartite graph. To minimize the effects of false positive interactions, the bait-prey relationships are indexed with reliability scores. Only non-redundant, reliable bicliques computed from the TAP bipartite graph are regarded as protein-complex cores. CACHET constructs protein complexes by including attachment proteins into the cores. We applied CACHET on large-scale TAP datasets and found that CACHET outperformed existing methods in terms of prediction accuracy (i.e., F-measure and functional homogeneity of predicted complexes). In addition, the protein complexes predicted by CACHET are equipped with core-attachment structures that provide useful biological insights into the inherent functional organization of protein complexes. Our supplementary material can be found at http://www1.i2r.a-star.edu.sg/~xlli/CACHET/CACHET.htm ; binary executables can also be found there. Supplementary Material is also available at www.liebertonline.com/cmb.
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Project description:DNA replication in Eukaryotes is a highly dynamic process that involves several dozens of proteins. Some of these proteins form stable complexes that are amenable to high-resolution structure determination by cryo-EM, thanks to the recent advent of the direct electron detector and powerful image analysis algorithm. But many of these proteins associate only transiently and flexibly, precluding traditional biochemical purification. We found that direct mixing of the component proteins followed by 2D and 3D image sorting can capture some very weakly interacting complexes. Even at 2D average level and at low resolution, EM images of these flexible complexes can provide important biological insights. It is often necessary to positively identify the feature-of-interest in a low resolution EM structure. We found that systematically fusing or inserting maltose binding protein (MBP) to selected proteins is highly effective in these situations. In this chapter, we describe the EM studies of several protein complexes involved in the eukaryotic DNA replication over the past decade or so. We suggest that some of the approaches used in these studies may be applicable to structural analysis of other biological systems.
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Project description:The operon coding for a respiratory quinol oxidase was cloned from thermoacidophilic archaebacterium Sulfolobus acidocaldarius. It contains three genes, soxA, soxB and soxC. The first two genes code for proteins related to the cytochrome c oxidase subunits II and I, respectively. soxC encodes a protein homologous to cytochrome b, which is a subunit of the mitochondrial and bacterial cytochrome c reductases and the chloroplast cytochrome b6f complex. soxA is preceded by a promoter and the genes are cotranscribed into a 4 kb mRNA. Their protein products form a complex which has been partially purified and has quinol oxidase activity. The reduced minus oxidized absorption spectrum of the complex has two maxima at 586 and 606 nm. The latter is typical of cytochrome c oxidase. The complex contains four haems A. Two haems belong to the 'cytochrome oxidase' part of the complex and two are probably bound to be apocytochrome b (SoxC) and responsible for the 586 nm absorption peak. The homology between the sox gene products and their mitochondrial counterparts suggests that energy conservation coupled to the quinol oxidation catalysed either by the Sulfolobus oxidase or two mitochondrial respiratory enzymes may have a similar mechanism.
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Project description:BackgroundCharacterizing the structural properties of protein interaction networks will help illuminate the organizational and functional relationships among elements in biological systems.ResultsIn this paper, we present a systematic exploration of the core/periphery structures in protein interaction networks (PINs). First, the concepts of cores and peripheries in PINs are defined. Then, computational methods are proposed to identify two types of cores, k-plex cores and star cores, from PINs. Application of these methods to a yeast protein interaction network has identified 110 k-plex cores and 109 star cores. We find that the k-plex cores consist of either "party" proteins, "date" proteins, or both. We also reveal that there are two classes of 1-peripheral proteins: "party" peripheries, which are more likely to be part of protein complex, and "connector" peripheries, which are more likely connected to different proteins or protein complexes. Our results also show that, besides connectivity, other variations in structural properties are related to the variation in biological properties. Furthermore, the negative correlation between evolutionary rate and connectivity are shown toysis. Moreover, the core/periphery structures help to reveal the existence of multiple levels of protein expression dynamics.ConclusionOur results show that both the structure and connectivity can be used to characterize topological properties in protein interaction networks, illuminating the functional organization of cellular systems.
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Project description:Genetic variation is the major mechanism behind adaptation and evolutionary change. As most proteins operate through interactions with other proteins, changes in protein complex composition and subunit sequence provide potentially new functions. Comparative genomics can reveal expansions, losses and sequence divergence within protein-coding genes, but in silico analysis cannot detect subunit substitutions or replacements of entire protein complexes. Insights into these fundamental evolutionary processes require broad and extensive comparative analyses, from both in silico and experimental evidence. Here, we combine data from both approaches and consider the gamut of possible protein complex compositional changes that arise during evolution, citing examples of complete conservation to partial and total replacement by functional analogues. We focus in part on complexes in trypanosomes as they represent one of the better studied non-animal/non-fungal lineages, but extend insights across the eukaryotes by extensive comparative genomic analysis. We argue that gene loss plays an important role in diversification of protein complexes and hence enhancement of eukaryotic diversity.
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Project description:BackgroundAll sequenced eukaryotic genomes have been shown to possess at least a few introns. This includes those unicellular organisms, which were previously suspected to be intron-less. Therefore, gene splicing must have been present at least in the last common ancestor of the eukaryotes. To explain the evolution of introns, basically two mutually exclusive concepts have been developed. The introns-early hypothesis says that already the very first protein-coding genes contained introns while the introns-late concept asserts that eukaryotic genes gained introns only after the emergence of the eukaryotic lineage. A very important aspect in this respect is the conservation of intron positions within homologous genes of different taxa.ResultsGenePainter is a standalone application for mapping gene structure information onto protein multiple sequence alignments. Based on the multiple sequence alignments the gene structures are aligned down to single nucleotides. GenePainter accounts for variable lengths in exons and introns, respects split codons at intron junctions and is able to handle sequencing and assembly errors, which are possible reasons for frame-shifts in exons and gaps in genome assemblies. Thus, even gene structures of considerably divergent proteins can properly be compared, as it is needed in phylogenetic analyses. Conserved intron positions can also be mapped to user-provided protein structures. For their visualization GenePainter provides scripts for the molecular graphics system PyMol.ConclusionsGenePainter is a tool to analyse gene structure conservation providing various visualization options. A stable version of GenePainter for all operating systems as well as documentation and example data are available at http://www.motorprotein.de/genepainter.html.
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