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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.

No MeSH data available.


Abundance and expression trends for proteins in complexesProteins within the identified complexes tend to be ubiquitously expressed across human tissues. Pie charts show the proportions of proteins with varying tissue expression patterns, from a recently published human tissue proteome map46, comparing: a, the full set of 20,258 human proteins, with b, the 2,131 proteins within the identified complexes. Consistent with these observations, 91% of the protein components in the complexes were expressed in >15 tissues in data from a reference human proteome23, compared to less than half (46%) of the 17,294 proteins in the overall reference set (Z-test p < 0.001). The distributions of average mRNA and protein abundances for all proteins identified and those within complexes are shown in panel c, mRNA abundances (data from EBI accession E-MTAB-1733) and d, protein abundances (data from PaxDb integrated dataset, 9606-H.sapiens_whole_organism-integrated_dataset). Evolutionarily ‘old’ proteins (defined by OMA as described in ref. 25 and mentioned earlier) tend towards higher abundances, even for proteins in reference complexes.
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Figure 10: Abundance and expression trends for proteins in complexesProteins within the identified complexes tend to be ubiquitously expressed across human tissues. Pie charts show the proportions of proteins with varying tissue expression patterns, from a recently published human tissue proteome map46, comparing: a, the full set of 20,258 human proteins, with b, the 2,131 proteins within the identified complexes. Consistent with these observations, 91% of the protein components in the complexes were expressed in >15 tissues in data from a reference human proteome23, compared to less than half (46%) of the 17,294 proteins in the overall reference set (Z-test p < 0.001). The distributions of average mRNA and protein abundances for all proteins identified and those within complexes are shown in panel c, mRNA abundances (data from EBI accession E-MTAB-1733) and d, protein abundances (data from PaxDb integrated dataset, 9606-H.sapiens_whole_organism-integrated_dataset). Evolutionarily ‘old’ proteins (defined by OMA as described in ref. 25 and mentioned earlier) tend towards higher abundances, even for proteins in reference complexes.

Mentions: These primordial complexes are present throughout the Opisthokonta supergroup (animals and fungi), estimated to be >1 billion years old29, and Plants (and presumably lost/significantly diverged among parasitic Protists). Reflecting this central importance, these complexes tend strongly to be ubiquitously expressed throughout all cell types and tissues (Extended Data Fig. 5a), are abundant (Extended Data Fig. 5b), and are enriched for associations to human disease and perturbation phenotypes in C. elegans (Supplementary Table 6). In comparison with other proteins in the 16,655 interactions, the older, conserved proteins present in these stable complexes have lower average domain complexity (p < 0.02; see Extended Methods), suggesting multi-domain architectures underlie more transient or tissue-specific interactions. Notably, whereas ‘mixed’ and ‘old’ complexes are enriched for functional associations with core cellular processes, such as metabolism (Extended Data Fig. 4c), the strictly metazoan complexes were far more likely to be linked to cell adhesion, organization and differentiation, consistent with roles in multicellularity. Reflecting these different evolutionary trajectories, ‘new’ clusters are substantially more enriched for cancer-related proteins (42%; 62/147; hypergeometric p ≤ 10−5) compared to strictly ‘old’ (15%; 53/344; p ≤ 10−3) clusters (Z-test < 0.0001) (Supplementary Table 7), have generally lower annotation rates (Extended Data Fig. 4b), and show different preponderances of protein domains (Extended Data Fig. 4c and Supplementary Table 6).


Panorama of ancient metazoan macromolecular complexes
Abundance and expression trends for proteins in complexesProteins within the identified complexes tend to be ubiquitously expressed across human tissues. Pie charts show the proportions of proteins with varying tissue expression patterns, from a recently published human tissue proteome map46, comparing: a, the full set of 20,258 human proteins, with b, the 2,131 proteins within the identified complexes. Consistent with these observations, 91% of the protein components in the complexes were expressed in >15 tissues in data from a reference human proteome23, compared to less than half (46%) of the 17,294 proteins in the overall reference set (Z-test p < 0.001). The distributions of average mRNA and protein abundances for all proteins identified and those within complexes are shown in panel c, mRNA abundances (data from EBI accession E-MTAB-1733) and d, protein abundances (data from PaxDb integrated dataset, 9606-H.sapiens_whole_organism-integrated_dataset). Evolutionarily ‘old’ proteins (defined by OMA as described in ref. 25 and mentioned earlier) tend towards higher abundances, even for proteins in reference complexes.
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Figure 10: Abundance and expression trends for proteins in complexesProteins within the identified complexes tend to be ubiquitously expressed across human tissues. Pie charts show the proportions of proteins with varying tissue expression patterns, from a recently published human tissue proteome map46, comparing: a, the full set of 20,258 human proteins, with b, the 2,131 proteins within the identified complexes. Consistent with these observations, 91% of the protein components in the complexes were expressed in >15 tissues in data from a reference human proteome23, compared to less than half (46%) of the 17,294 proteins in the overall reference set (Z-test p < 0.001). The distributions of average mRNA and protein abundances for all proteins identified and those within complexes are shown in panel c, mRNA abundances (data from EBI accession E-MTAB-1733) and d, protein abundances (data from PaxDb integrated dataset, 9606-H.sapiens_whole_organism-integrated_dataset). Evolutionarily ‘old’ proteins (defined by OMA as described in ref. 25 and mentioned earlier) tend towards higher abundances, even for proteins in reference complexes.
Mentions: These primordial complexes are present throughout the Opisthokonta supergroup (animals and fungi), estimated to be >1 billion years old29, and Plants (and presumably lost/significantly diverged among parasitic Protists). Reflecting this central importance, these complexes tend strongly to be ubiquitously expressed throughout all cell types and tissues (Extended Data Fig. 5a), are abundant (Extended Data Fig. 5b), and are enriched for associations to human disease and perturbation phenotypes in C. elegans (Supplementary Table 6). In comparison with other proteins in the 16,655 interactions, the older, conserved proteins present in these stable complexes have lower average domain complexity (p < 0.02; see Extended Methods), suggesting multi-domain architectures underlie more transient or tissue-specific interactions. Notably, whereas ‘mixed’ and ‘old’ complexes are enriched for functional associations with core cellular processes, such as metabolism (Extended Data Fig. 4c), the strictly metazoan complexes were far more likely to be linked to cell adhesion, organization and differentiation, consistent with roles in multicellularity. Reflecting these different evolutionary trajectories, ‘new’ clusters are substantially more enriched for cancer-related proteins (42%; 62/147; hypergeometric p ≤ 10−5) compared to strictly ‘old’ (15%; 53/344; p ≤ 10−3) clusters (Z-test < 0.0001) (Supplementary Table 7), have generally lower annotation rates (Extended Data Fig. 4b), and show different preponderances of protein domains (Extended Data Fig. 4c and Supplementary Table 6).

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.