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Triangle network motifs predict complexes by complementing high-error interactomes with structural information.

ABSTRACT: BACKGROUND: A lot of high-throughput studies produce protein-protein interaction networks (PPINs) with many errors and missing information. Even for genome-wide approaches, there is often a low overlap between PPINs produced by different studies. Second-level neighbors separated by two protein-protein interactions (PPIs) were previously used for predicting protein function and finding complexes in high-error PPINs. We retrieve second level neighbors in PPINs, and complement these with structural domain-domain interactions (SDDIs) representing binding evidence on proteins, forming PPI-SDDI-PPI triangles. RESULTS: We find low overlap between PPINs, SDDIs and known complexes, all well below 10%. We evaluate the overlap of PPI-SDDI-PPI triangles with known complexes from Munich Information center for Protein Sequences (MIPS). PPI-SDDI-PPI triangles have ~20 times higher overlap with MIPS complexes than using second-level neighbors in PPINs without SDDIs. The biological interpretation for triangles is that a SDDI causes two proteins to be observed with common interaction partners in high-throughput experiments. The relatively few SDDIs overlapping with PPINs are part of highly connected SDDI components, and are more likely to be detected in experimental studies. We demonstrate the utility of PPI-SDDI-PPI triangles by reconstructing myosin-actin processes in the nucleus, cytoplasm, and cytoskeleton, which were not obvious in the original PPIN. Using other complementary datatypes in place of SDDIs to form triangles, such as PubMed co-occurrences or threading information, results in a similar ability to find protein complexes. CONCLUSION: Given high-error PPINs with missing information, triangles of mixed datatypes are a promising direction for finding protein complexes. Integrating PPINs with SDDIs improves finding complexes. Structural SDDIs partially explain the high functional similarity of second-level neighbors in PPINs. We estimate that relatively little structural information would be sufficient for finding complexes involving most of the proteins and interactions in a typical PPIN.

SUBMITTER: Andreopoulos B

PROVIDER: S-EPMC2714575 | biostudies-literature | 2009

REPOSITORIES: biostudies-literature

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Triangle network motifs predict complexes by complementing high-error interactomes with structural information.

Andreopoulos Bill B Winter Christof C Labudde Dirk D Schroeder Michael M

BMC bioinformatics 20090627

<h4>Background</h4>A lot of high-throughput studies produce protein-protein interaction networks (PPINs) with many errors and missing information. Even for genome-wide approaches, there is often a low overlap between PPINs produced by different studies. Second-level neighbors separated by two protein-protein interactions (PPIs) were previously used for predicting protein function and finding complexes in high-error PPINs. We retrieve second level neighbors in PPINs, and complement these with str ...[more]

PMID: 19558694

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Project description:Cognitive impairment affects about 50% of multiple sclerosis (MS) patients, but the mechanisms underlying this remain unclear. The default mode network (DMN) has been linked with cognition, but in MS its role is still poorly understood. Moreover, within an extended DMN network including the cerebellum (CBL-DMN), the contribution of cortico-cerebellar connectivity to MS cognitive performance remains unexplored. The present study investigated associations of DMN and CBL-DMN structural connectivity with cognitive processing speed in MS, in both cognitively impaired (CIMS) and cognitively preserved (CPMS) MS patients. 68 MS patients and 22 healthy controls (HCs) completed a symbol digit modalities test (SDMT) and had 3T brain magnetic resonance imaging (MRI) scans that included a diffusion weighted imaging protocol. DMN and CBL-DMN tracts were reconstructed with probabilistic tractography. These networks (DMN and CBL-DMN) and the cortico-cerebellar tracts alone were modeled using a graph theoretical approach with fractional anisotropy (FA) as the weighting factor. Brain parenchymal fraction (BPF) was also calculated. In CIMS SDMT scores strongly correlated with the FA-weighted global efficiency (GE) of the network [GE(CBL-DMN): ρ = 0.87, R 2 = 0.76, p < 0.001; GE(DMN): ρ = 0.82, R 2 = 0.67, p < 0.001; GE(CBL): ρ = 0.80, R 2 = 0.64, p < 0.001]. In CPMS the correlation between these measures was significantly lower [GE(CBL-DMN): ρ = 0.51, R 2 = 0.26, p < 0.001; GE(DMN): ρ = 0.48, R 2 = 0.23, p = 0.001; GE(CBL): ρ = 0.52, R 2 = 0.27, p < 0.001] and SDMT scores correlated most with BPF (ρ = 0.57, R 2 = 0.33, p < 0.001). In a multivariable regression model where SDMT was the independent variable, FA-weighted GE was the only significant explanatory variable in CIMS, while in CPMS BPF and expanded disability status scale were significant. No significant correlation was found in HC between SDMT scores, MRI or network measures. DMN structural GE is related to cognitive performance in MS, and results of CBL-DMN suggest that the cerebellum structural connectivity to the DMN plays an important role in information processing speed decline.

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Triangle network motifs predict complexes by complementing high-error interactomes with structural information.

Publications

Triangle network motifs predict complexes by complementing high-error interactomes with structural information.

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