Using an evolutionary approach, the researchers detected proteins that \u201ccoevolve\u201d with ACE2 in mammals as a way to identify networks of proteins that likely interact with ACE2 during its normal functions in the human body. Their rationale is that disruptions caused by COVID-19 in these normal functions of ACE2 could contribute to the unusual pathologies of the disease.<\/p>\n
COVID-19, ACE2, and protein partners<\/strong><\/h3>\nThe method used by the researchers revealed a number of candidate protein partners for ACE2 that have not previously been identified as ACE2 interactors, but which could have direct bearing on the complications experienced by people infected with the virus. These COVID-related complications can include excessive blood clotting as well as an overactive inflammation response known as a \u201ccytokine storm\u201d\u2014both of which can cause tissue and organ damage.<\/p>\n
For example, one hallmark of severe COVID-19 is abnormal blood coagulation throughout the body. The team\u2019s research revealed noteworthy connections between ACE2 and key proteins involved in the coagulation pathway. Another protein, Clusterin, which plays a significant role in \u201cquality control\u201d in the blood by removing misfolded proteins, strongly coevolves with ACE2\u2014implying that they interact with each other biologically. Several proteins involved in cytokine signaling appear to coevolve with ACE2 as well.<\/p>\n
\u201cWe propose that ACE2 has novel protein interactions that are disrupted during SARS-CoV-2 infection, contributing to the spectrum of COVID-19 pathologies,\u201d Werren says. Finding that ACE2\u2019s evolutionary partners are involved in blood coagulation and cytokine signaling is consistent with this possibility.<\/p>\n
\u201cOnce we uncovered the evolutionary rate partners of ACE2, their potential clinical relevance was immediately clear.\u201d<\/div>\n\u201cThese candidate protein interactions will need to be validated,\u201d Werren says. \u201cBut if supported, our findings could inform development of better treatments and therapeutics for COVID-19 and chronic complications that may arise.\u201d<\/p>\n
As an evolutionary geneticist, Werren focuses on the interaction of genomes in symbiotic or parasitic relationships. When the COVID-19 pandemic hit, Werren received a grant<\/a> from the National Science Foundation\u2019s Rapid Response Research program to study the ACE2\u2019s protein interactions and its network of coevolving proteins. The University\u2019s Nathaniel and Helen Wisch Chair Research Fund, meanwhile, helped support Varela\u2019s and Cheng\u2019s participation.<\/p>\n\u201cWorking on this project was a great opportunity for me,\u201d says Varela, the study\u2019s first author, who started researching protein-protein interactions in the Werren Lab during his sophomore year at Rochester. \u201cOnce we uncovered the evolutionary rate partners of ACE2, their potential clinical relevance was immediately clear.\u201d<\/p>\n
Evolutionary approach to detecting protein partners and interactions<\/strong><\/h3>\nWerren and his colleagues used a computational and evolutionary approach called evolutionary rate correlation (ERC). The underlying concept is that proteins with similar rates of change during evolution are more likely to have functional interactions. For example, if you look at a phylogenetic tree depicting the evolutionary relationships among mammals, when one protein evolves quickly in a particular species, a protein with which it functionally interacts will tend to evolve quickly as well, and vice versa.<\/p>\n
Werren previously applied the ERC method to protein interactions involved in mitochondrial function. Mitochondria are cellular structures that, among other functions, produce energy for the cell. In that study<\/a>, the ERC method accurately predicted nuclear encoded proteins known to interact with mitochondria, and also detected proteins not previously known to have mitochondrial function.<\/p>\nBiomedical researchers currently harness a number of powerful tools for detecting and exploring proteins that interact with each other in biological processes. These include genetic screens, protein coprecipitation, and proteomic profiling.<\/p>\n
Evolutionary approaches such as ERC have the potential to become useful additions to the biomedical research toolkit. Werren and his team are now expanding the number of proteins in their analysis. He says, \u201cWe hope to produce a more extensive database for researchers so they can explore coevolving partners for proteins of interest in their research.\u201d<\/p>\n
\nRead more<\/strong><\/h3>\n\n![\"bat](\"https:\/\/www.rochester.edu\/newscenter\/wp-content\/uploads\/2020\/07\/fea-bats-clues-covid-19.jpg\")
Bats offer clues to treating COVID-19<\/strong><\/a>
\nBats carry many viruses, including the one behind COVID-19, without becoming ill. University of Rochester biologists are studying the immune system of bats to find potential ways to \u201cmimic\u201d that system in humans.<\/span><\/div>\n
\u201cThese candidate protein interactions will need to be validated,\u201d Werren says. \u201cBut if supported, our findings could inform development of better treatments and therapeutics for COVID-19 and chronic complications that may arise.\u201d<\/p>\n
As an evolutionary geneticist, Werren focuses on the interaction of genomes in symbiotic or parasitic relationships. When the COVID-19 pandemic hit, Werren received a grant<\/a> from the National Science Foundation\u2019s Rapid Response Research program to study the ACE2\u2019s protein interactions and its network of coevolving proteins. The University\u2019s Nathaniel and Helen Wisch Chair Research Fund, meanwhile, helped support Varela\u2019s and Cheng\u2019s participation.<\/p>\n \u201cWorking on this project was a great opportunity for me,\u201d says Varela, the study\u2019s first author, who started researching protein-protein interactions in the Werren Lab during his sophomore year at Rochester. \u201cOnce we uncovered the evolutionary rate partners of ACE2, their potential clinical relevance was immediately clear.\u201d<\/p>\n Werren and his colleagues used a computational and evolutionary approach called evolutionary rate correlation (ERC). The underlying concept is that proteins with similar rates of change during evolution are more likely to have functional interactions. For example, if you look at a phylogenetic tree depicting the evolutionary relationships among mammals, when one protein evolves quickly in a particular species, a protein with which it functionally interacts will tend to evolve quickly as well, and vice versa.<\/p>\n Werren previously applied the ERC method to protein interactions involved in mitochondrial function. Mitochondria are cellular structures that, among other functions, produce energy for the cell. In that study<\/a>, the ERC method accurately predicted nuclear encoded proteins known to interact with mitochondria, and also detected proteins not previously known to have mitochondrial function.<\/p>\n Biomedical researchers currently harness a number of powerful tools for detecting and exploring proteins that interact with each other in biological processes. These include genetic screens, protein coprecipitation, and proteomic profiling.<\/p>\n Evolutionary approaches such as ERC have the potential to become useful additions to the biomedical research toolkit. Werren and his team are now expanding the number of proteins in their analysis. He says, \u201cWe hope to produce a more extensive database for researchers so they can explore coevolving partners for proteins of interest in their research.\u201d<\/p>\nEvolutionary approach to detecting protein partners and interactions<\/strong><\/h3>\n
\nRead more<\/strong><\/h3>\n
Bats offer clues to treating COVID-19<\/strong><\/a>
\nBats carry many viruses, including the one behind COVID-19, without becoming ill. University of Rochester biologists are studying the immune system of bats to find potential ways to \u201cmimic\u201d that system in humans.<\/span><\/div>\n
![\"illustration](\"https:\/\/www.rochester.edu\/newscenter\/wp-content\/uploads\/2020\/07\/2020_july_ace2_gettyimages-1249068502-170667a.jpg\")
Rochester biologists selected for \u2018rapid research\u2019 on COVID-19<\/strong><\/a>![\"Illustration](\"https:\/\/www.rochester.edu\/newscenter\/wp-content\/uploads\/2020\/04\/fea-rna-research-coronavirus.jpg\")
COVID-19 vaccine: What\u2019s RNA research got to do with it?<\/strong><\/a>