Structural libraries of protein models for multiple species to understand evolution of the renin-angiotensin system

Abstract

The details of protein pathways at a structural level provides a bridge between genetics/molecular biology and physiology. The renin-angiotensin system is involved in many physiological pathways with informative structural details in multiple components. Few studies have been performed assessing structural knowledge across the system. This assessment allows use of bioinformatics tools to fill in missing structural voids. In this paper we detail known structures of the renin-angiotensin system and use computational approaches to estimate and model components that do not have their protein structures defined. With the subsequent large library of protein structures, we then created a species specific protein library for human, mouse, rat, bovine, zebrafish, and chicken for the system. The rat structural system allowed for rapid screening of genetic variants from 51 commonly used rat strains, identifying amino acid variants in Angiotensinogen, ACE2, and AT1b that are in contact positions with other macromolecules. We believe the structural map will be of value for other researchers to understand their experimental data in the context of an environment for multiple proteins, providing pdb files of proteins for the renin-angiotensin system in six species. With detailed structural descriptions of each protein, it is easier to assess a species for use in translating human diseases with animal models. Additionally, as whole genome sequencing continues to decrease in cost, tools such as molecular modeling will gain use as an initial step in designing efficient hypothesis driven research, addressing potential functional outcomes of genetic variants with precompiled protein libraries aiding in rapid characterizations.

An intestinal cell type in zebrafish is the nexus for the SARS-CoV-2 receptor and the Renin-Angiotensin-Aldosterone System that contributes to COVID-19 comorbidities

“…The Ace inhibitor enalapril, used to treat patients with high blood pressure, causes intraocular blood vessels to dilate in zebrafish (Kitambi et al, 2009) as expected from conserved functions. The fact that several different Ace inhibitors have similar effects in humans and zebrafish supports both the physiological conservation of the Ace (Prokop et al, 2015).…”

The SARS-CoV-2 receptor and other key components of the Renin-Angiotensin-Aldosterone System related to COVID-19 are expressed in enterocytes in larval zebrafish

“…The Ace inhibitor blood pressure medication enalapril causes intraocular blood vessels to dilate in zebrafish ( Kitambi et al, 2009 ) as expected from conserved functions. The fact that Ace inhibitors have similar effects in humans and zebrafish supports physiological conservation of the Ace system ( Prokop et al, 2015 ).…”

SARS-CoV2 (COVID-19) Structural/Evolution Dynamicome: Insights into functional evolution and human genomics

“…The biophysical and structural evidence suggested that SARS-CoV-2 may bind ACE2 with a much higher affinity than SARS-CoV (Wrapp et al, 2020). Our group had previously investigated the evolution of ACE2 throughout species including mapping variants within rat populations (Prokop et al, 2015), a model system for studying the Renin-Angiotensin Aldosterone system (known as the RAAS). We have expanded those tools here, generating ACE2 models for 235 species from mammals to birds/fish, where each of the models are energy minimized with the S protein interaction.…”