Coevolution Reveals a Network of Human Proteins Originating with Multicellularity

Bezginov, Alexandr; Clark, Greg W.; Charlebois, Robert L.; Dar, Vaqaar-un-Nisa; Tillier, Elisabeth R. M.

doi:10.1093/molbev/mss218

Cited by 23 publications

(34 citation statements)

References 54 publications

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“…Consistent with our findings, it was previously shown that the node degree in interaction networks was higher for more ancient taxonomic nodes (41) and ancient proteins had high connectivity and centrality in protein interactomes (42). Moreover, it was observed that protein interaction networks partitioned into two subnetworks: one corresponding to the most ancient interactions and one related to the recently emerged interactions in animal evolution that are involved in cell division and cell communication (41). A high level of horizontal gene transfer between species, a mechanism by which new interactions may emerge, is also characteristic for early stages of evolution (43).…”

Section: Tracing Back the Evolution Of Protein-binding Sites To The Osupporting

confidence: 93%

“…In addition, Bacteria have many specific transcription regulators that are involved in the xenobiotics-resistance response, as in the case of the HTH_XRE superfamily. Consistent with our findings, it was previously shown that the node degree in interaction networks was higher for more ancient taxonomic nodes (41) and ancient proteins had high connectivity and centrality in protein interactomes (42). Moreover, it was observed that protein interaction networks partitioned into two subnetworks: one corresponding to the most ancient interactions and one related to the recently emerged interactions in animal evolution that are involved in cell division and cell communication (41).…”

Section: Tracing Back the Evolution Of Protein-binding Sites To The Osupporting

confidence: 91%

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Structural Perspectives on the Evolutionary Expansion of Unique Protein-Protein Binding Sites

Goncearenco

Shaytan

Shoemaker

et al. 2015

Biophysical Journal

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Structures of protein complexes provide atomistic insights into protein interactions. Human proteins represent a quarter of all structures in the Protein Data Bank; however, available protein complexes cover less than 10% of the human proteome. Although it is theoretically possible to infer interactions in human proteins based on structures of homologous protein complexes, it is still unclear to what extent protein interactions and binding sites are conserved, and whether protein complexes from remotely related species can be used to infer interactions and binding sites. We considered biological units of protein complexes and clustered protein-protein binding sites into similarity groups based on their structure and sequence, which allowed us to identify unique binding sites. We showed that the growth rate of the number of unique binding sites in the Protein Data Bank was much slower than the growth rate of the number of structural complexes. Next, we investigated the evolutionary roots of unique binding sites and identified the major phyletic branches with the largest expansion in the number of novel binding sites. We found that many binding sites could be traced to the universal common ancestor of all cellular organisms, whereas relatively few binding sites emerged at the major evolutionary branching points. We analyzed the physicochemical properties of unique binding sites and found that the most ancient sites were the largest in size, involved many salt bridges, and were the most compact and least planar. In contrast, binding sites that appeared more recently in the evolution of eukaryotes were characterized by a larger fraction of polar and aromatic residues, and were less compact and more planar, possibly due to their more transient nature and roles in signaling processes.

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Section: Tracing Back the Evolution Of Protein-binding Sites To The Osupporting

confidence: 93%

Section: Tracing Back the Evolution Of Protein-binding Sites To The Osupporting

confidence: 91%

Structural Perspectives on the Evolutionary Expansion of Unique Protein-Protein Binding Sites

Goncearenco

Shaytan

Shoemaker

et al. 2015

Biophysical Journal

View full text Add to dashboard Cite

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“…In addition, we performed an evolutionary rate ratio analysis, as described in a previous study. 44 Details of data and analyses were provided in our previous study. 36 …”

Section: Computing Selective Pressure and Evolutionary Ratesmentioning

confidence: 99%

“…Furthermore, we performed an evolutionary distance analysis by comparing human sequences with orthologous sequences from other animals, as described previously. 44 …”

Section: Inferring Protein Evolutionary Originsmentioning

confidence: 99%

Proteome-Scale Investigation of Protein Allosteric Regulation Perturbed by Somatic Mutations in 7,000 Cancer Genomes

Shen

Cheng

Song

et al. 2017

The American Journal of Human Genetics

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The allosteric regulation triggering the protein's functional activity via conformational changes is an intrinsic function of protein under many physiological and pathological conditions, including cancer. Identification of the biological effects of specific somatic variants on allosteric proteins and the phenotypes that they alter during tumor initiation and progression is a central challenge for cancer genomes in the post-genomic era. Here, we mapped more than 47,000 somatic missense mutations observed in approximately 7,000 tumor-normal matched samples across 33 cancer types into protein allosteric sites to prioritize the mutated allosteric proteins and we tested our prediction in cancer cell lines. We found that the deleterious mutations identified in cancer genomes were more significantly enriched at protein allosteric sites than tolerated mutations, suggesting a critical role for protein allosteric variants in cancer. Next, we developed a statistical approach, namely AlloDriver, and further identified 15 potential mutated allosteric proteins during pan-cancer and individual cancer-type analyses. More importantly, we experimentally confirmed that p.Pro360Ala on PDE10A played a potential oncogenic role in mediating tumorigenesis in non-small cell lung cancer (NSCLC). In summary, these findings shed light on the role of allosteric regulation during tumorigenesis and provide a useful tool for the timely development of targeted cancer therapies.

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“…The relative rates of evolution for the proteins and their domains were calculated as described earlier 26 . Ortholog groups were obtain using the OMA Browser 27 and alignments were obtained with MAFFT 28 .…”

Section: Methodsmentioning

confidence: 99%

Structural pliability adjacent to the kinase domain highlights contribution of FAK1 IDRs to cytoskeletal remodeling

Kathiriya

Pathak

Bezginov

et al. 2017

Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics

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Therapeutic protein kinase inhibitors are designed on the basis of kinase structures. Here, we define intrinsically disordered regions (IDRs) in structurally hybrid kinases. We reveal that 65% of kinases have an IDR adjacent to their kinase domain (KD). These IDRs are evolutionarily more conserved than IDRs distant to KDs. Strikingly, 36 kinases have adjacent IDRs extending into their KDs, defining a unique structural and functional subset of the kinome. Functional network analysis of this subset of the kinome uncovered FAK1 as topologically the most connected hub kinase. We identify that KD-flanking IDR of FAK1 is more conserved and undergoes more post-translational modifications than other IDRs. It preferentially interacts with proteins regulating scaffolding and kinase activity, which contribute to cytoskeletal remodeling. In summary, spatially and evolutionarily conserved IDRs in kinases may influence their functions, which can be exploited for targeted therapies in diseases including those that involve aberrant cytoskeletal remodeling.

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Coevolution Reveals a Network of Human Proteins Originating with Multicellularity

Cited by 23 publications

References 54 publications

Structural Perspectives on the Evolutionary Expansion of Unique Protein-Protein Binding Sites

Structural Perspectives on the Evolutionary Expansion of Unique Protein-Protein Binding Sites

Proteome-Scale Investigation of Protein Allosteric Regulation Perturbed by Somatic Mutations in 7,000 Cancer Genomes

Structural pliability adjacent to the kinase domain highlights contribution of FAK1 IDRs to cytoskeletal remodeling

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