Gene variants of coagulation related proteins that interact with SARS-CoV-2

Abstract

Thrombosis is a recognized complication of Coronavirus disease of 2019 (COVID-19) and is often associated with poor prognosis. There is a well-recognized link between coagulation and inflammation, however, the extent of thrombotic events associated with COVID-19 warrants further investigation. Poly(A) Binding Protein Cytoplasmic 4 (PABPC4), Serine/Cysteine Proteinase Inhibitor Clade G Member 1 (SERPING1) and Vitamin K epOxide Reductase Complex subunit 1 (VKORC1), which are all proteins linked to coagulation, have been shown to interact with SARS proteins. We computationally examined the interaction of these with SARS-CoV-2 proteins and, in the case of VKORC1, we describe its binding to ORF7a in detail. We examined the occurrence of variants of each of these proteins across populations and interrogated their potential contribution to COVID-19 severity. Potential mechanisms, by which some of these variants may contribute to disease, are proposed. Some of these variants are prevalent in minority groups that are disproportionally affected by severe COVID-19. Therefore, we are proposing that further investigation around these variants may lead to better understanding of disease pathogenesis in minority groups and more informed therapeutic approaches.

Fig 1. Graphic summary of ORF7a-VKORC1 interaction and possible effects.

The interaction between ORF7a and VKORC1 and possible effects of this interaction.

Fig 2. Predicted dock of VKORC1 and ORF7a transmembrane domain.

A. Five protein-protein docks depict one main binding site (teal, grey, yellow, green, blue). B. The lowest interface-energy model is shown as a surface representation. C. The lowest interface-energy model, with side chains shown in wheat for amino acids at the interface. D. Another view of the lowest interface-energy model, with side chains shown in wheat at the interface and hydrophobics shown in blue. Amino acids of VKORC1 necessary for vitamin K binding (83F, 80N, 135C, 55F) or warfarin binding (134V, 133I) are given in green.

Fig 3. Plots of interface energy (I_sc) against interface root mean square error (I_rms).

Each point represents a complex formed from one of the top 5 ZDock outputs of VKORC1 and ORF7a proteins, using 10,000 decoys. All plots form energy funnels.

Fig 4. Locations of warfarin dosage affecting nonsynonymous variants in VKORC1.

VKORC1 is shown in salmon, while ORF7a is shown in grey. Warfarin dosage affecting nonsynonymous variants are shown in blue. Active site amino acids are shown in green.

Fig 5. Structural alignment of ORF7a, CXADR, and PCDH1 proteins.

The alignment is largely confined to the beta sheets.