Abstract
Viruses often encode proteins that mimic host proteins in order to facilitate infection. Little work has been done to understand the potential mimicry of the SARS-CoV-2, SARS-CoV, and MERS-CoV spike proteins, particularly the receptor-binding motifs, which could be important in determining tropism and druggability of the virus. Peptide and epitope motifs have been detected on coronavirus spike proteins using sequence homology approaches; however, comparing the three-dimensional shape of the protein has been shown as more informative in predicting mimicry than sequence-based comparisons. Here, we use structural bioinformatics software to characterize potential mimicry of the three coronavirus spike protein receptor-binding motifs. We utilize sequence-independent alignment tools to compare structurally known protein models with the receptor-binding motifs and verify potential mimicked interactions with protein docking simulations. Both human and non-human proteins were returned for all three receptor-binding motifs. For example, all three were similar to several proteins containing EGF-like domains: some of which are endogenous to humans, such as thrombomodulin, and others exogenous, such as Plasmodium falciparum MSP-1. Similarity to human proteins may reveal which pathways the spike protein is co-opting, while analogous non-human proteins may indicate shared host interaction partners and overlapping antibody cross-reactivity. These findings can help guide experimental efforts to further understand potential interactions between human and coronavirus proteins.
Highlights
Viruses have long been known to utilize molecular mimicry of host proteins to interrupt and exploit host biochemical pathways during infection [1,2]
Several models of the spike protein for each of the highly pathogenic coronaviruses have been experimentally determined; many of them are missing residues due to the difficulty in resolving the structure of flexible protein motifs [37]. To overcome this issue and obtain a representative three-dimensional model of each spike receptor-binding motif (RBM), we used ProtCHOIR, a recently developed pipeline to automate the modelling of homooligomers, to model each trimeric spike protein and, subsequently, manually selected the RBM residues for each coronavirus (Fig. 1)
We built representative models of the spike RBMs and tested structural changes in the SARS-CoV-2 RBM induced by recently recorded mutations, which had little effect on overall RBM structure
Summary
Viruses have long been known to utilize molecular mimicry of host proteins to interrupt and exploit host biochemical pathways during infection [1,2]. Alongside the need to employ host machinery for the viral replication cycle, the evolution of viral protein motifs that resemble host proteins can result in new virulence mechanisms, such as inducing inflammation and evading the immune system [3]. Coronaviruses, in particular, have been suspected to have acquired human protein mimics throughout the long record of human coronavirus infections [4,5].
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