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Panorama of ancient metazoan macromolecular complexes

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ABSTRACT

Macromolecular complexes are essential to conserved biological processes, but their prevalence across animals is unclear. By combining extensive biochemical fractionation with quantitative mass spectrometry, we directly examined the composition of soluble multiprotein complexes among diverse metazoan models. Using an integrative approach, we then generated a draft conservation map consisting of >1 million putative high-confidence co-complex interactions for species with fully sequenced genomes that encompasses functional modules present broadly across all extant animals. Clustering revealed a spectrum of conservation, ranging from ancient Eukaryal assemblies likely serving cellular housekeeping roles for at least 1 billion years, ancestral complexes that have accrued contemporary components, and rarer metazoan innovations linked to multicellularity. We validated these projections by independent co-fractionation experiments in evolutionarily distant species, by affinity-purification and by functional analyses. The comprehensiveness, centrality and modularity of these reconstructed interactomes reflect their fundamental mechanistic significance and adaptive value to animal cell systems.

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Properties of protein elution profilesa, Distribution of global protein tissue expression pattern similarity, measured as the Pearson correlation coefficient of protein abundance across 30 human tissues23, showing markedly higher correlations for 16,468 protein-protein pairs of putative co-complex interaction partners compared to the same number of randomized pairs of proteins in the network which were not predicted to interact. b, Heatmap illustrating the low to moderate cross-species Spearman’s rank correlation coefficients in the elution profiles observed between orthologous proteins during mixed-bed ion exchange chromatography (IEX-HPLC) under standardized conditions, highlighting the shift in absolute chromatographic retention times in different species. This variation indicates that the conservation of co-fractionation by putatively interacting proteins is not merely a trivial result stemming from fixed column retention times. c, The degree of co-fractionation is measured as the correlation coefficient between elution profiles. Spatial proximity is calculated from the mean of residue pair distances between components of multisubunit complexes with known 3D structures (see Extended Methods).
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Figure 7: Properties of protein elution profilesa, Distribution of global protein tissue expression pattern similarity, measured as the Pearson correlation coefficient of protein abundance across 30 human tissues23, showing markedly higher correlations for 16,468 protein-protein pairs of putative co-complex interaction partners compared to the same number of randomized pairs of proteins in the network which were not predicted to interact. b, Heatmap illustrating the low to moderate cross-species Spearman’s rank correlation coefficients in the elution profiles observed between orthologous proteins during mixed-bed ion exchange chromatography (IEX-HPLC) under standardized conditions, highlighting the shift in absolute chromatographic retention times in different species. This variation indicates that the conservation of co-fractionation by putatively interacting proteins is not merely a trivial result stemming from fixed column retention times. c, The degree of co-fractionation is measured as the correlation coefficient between elution profiles. Spatial proximity is calculated from the mean of residue pair distances between components of multisubunit complexes with known 3D structures (see Extended Methods).

Mentions: Multiple lines of evidence support the quality of the network: Reference complexes withheld during training were reconstructed with higher precision and recall (Fig. 2b; see Extended Data Fig. 1c) relative to our human-only map6. The interacting proteins were also 6-fold enriched (hypergeometric p-value < 10−24) for shared subcellular localization annotations in the Human Protein Atlas Database21, 21-fold enriched (p-value < 10−56) for shared disease associations in OMIM22, and showed highly correlated human tissue proteome abundance profiles23 (Extended Data Fig. 2a).


Panorama of ancient metazoan macromolecular complexes
Properties of protein elution profilesa, Distribution of global protein tissue expression pattern similarity, measured as the Pearson correlation coefficient of protein abundance across 30 human tissues23, showing markedly higher correlations for 16,468 protein-protein pairs of putative co-complex interaction partners compared to the same number of randomized pairs of proteins in the network which were not predicted to interact. b, Heatmap illustrating the low to moderate cross-species Spearman’s rank correlation coefficients in the elution profiles observed between orthologous proteins during mixed-bed ion exchange chromatography (IEX-HPLC) under standardized conditions, highlighting the shift in absolute chromatographic retention times in different species. This variation indicates that the conservation of co-fractionation by putatively interacting proteins is not merely a trivial result stemming from fixed column retention times. c, The degree of co-fractionation is measured as the correlation coefficient between elution profiles. Spatial proximity is calculated from the mean of residue pair distances between components of multisubunit complexes with known 3D structures (see Extended Methods).
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC5036527&req=5

Figure 7: Properties of protein elution profilesa, Distribution of global protein tissue expression pattern similarity, measured as the Pearson correlation coefficient of protein abundance across 30 human tissues23, showing markedly higher correlations for 16,468 protein-protein pairs of putative co-complex interaction partners compared to the same number of randomized pairs of proteins in the network which were not predicted to interact. b, Heatmap illustrating the low to moderate cross-species Spearman’s rank correlation coefficients in the elution profiles observed between orthologous proteins during mixed-bed ion exchange chromatography (IEX-HPLC) under standardized conditions, highlighting the shift in absolute chromatographic retention times in different species. This variation indicates that the conservation of co-fractionation by putatively interacting proteins is not merely a trivial result stemming from fixed column retention times. c, The degree of co-fractionation is measured as the correlation coefficient between elution profiles. Spatial proximity is calculated from the mean of residue pair distances between components of multisubunit complexes with known 3D structures (see Extended Methods).
Mentions: Multiple lines of evidence support the quality of the network: Reference complexes withheld during training were reconstructed with higher precision and recall (Fig. 2b; see Extended Data Fig. 1c) relative to our human-only map6. The interacting proteins were also 6-fold enriched (hypergeometric p-value < 10−24) for shared subcellular localization annotations in the Human Protein Atlas Database21, 21-fold enriched (p-value < 10−56) for shared disease associations in OMIM22, and showed highly correlated human tissue proteome abundance profiles23 (Extended Data Fig. 2a).

View Article: PubMed Central - PubMed

ABSTRACT

Macromolecular complexes are essential to conserved biological processes, but their prevalence across animals is unclear. By combining extensive biochemical fractionation with quantitative mass spectrometry, we directly examined the composition of soluble multiprotein complexes among diverse metazoan models. Using an integrative approach, we then generated a draft conservation map consisting of &gt;1 million putative high-confidence co-complex interactions for species with fully sequenced genomes that encompasses functional modules present broadly across all extant animals. Clustering revealed a spectrum of conservation, ranging from ancient Eukaryal assemblies likely serving cellular housekeeping roles for at least 1 billion years, ancestral complexes that have accrued contemporary components, and rarer metazoan innovations linked to multicellularity. We validated these projections by independent co-fractionation experiments in evolutionarily distant species, by affinity-purification and by functional analyses. The comprehensiveness, centrality and modularity of these reconstructed interactomes reflect their fundamental mechanistic significance and adaptive value to animal cell systems.

No MeSH data available.


Related in: MedlinePlus