Are the integrin binding motifs within SARS CoV-2 spike protein and MHC class II alleles playing the key role in COVID-19?, 2023, Gerencer & McGuffin

[SNT Gatchaman]

Are the integrin binding motifs within SARS CoV-2 spike protein and MHC class II alleles playing the key role in COVID-19?
Gerencer, Marijan; McGuffin, Liam J.

The previous studies on the RGD motif (aa403-405) within the SARS CoV-2 spike (S) protein receptor binding domain (RBD) suggest that the RGD motif binding integrin(s) may play an important role in infection of the host cells. We also discussed the possible role of two other integrin binding motifs that are present in S protein: LDI (aa585-587) and ECD (661-663), the motifs used by some other viruses in the course of infection.

The MultiFOLD models for protein structure analysis have shown that the ECD motif is clearly accessible in the S protein, whereas the RGD and LDI motifs are partially accessible. Furthermore, the amino acids that are present in Epstein-Barr virus protein (EBV) gp42 playing very important role in binding to the HLA-DRB1 molecule and in the subsequent immune response evasion, are also present in the S protein heptad repeat-2. Our MultiFOLD model analyses have shown that these amino acids are clearly accessible on the surface in each S protein chain as monomers and in the homotrimer complex and bind to HLA-DRB1 b chain. Therefore, they may have the identical role in SARS CoV-2 immune evasion as in EBV infection. The prediction analyses of the MHC class II binding peptides within the S protein have shown that the RGD motif is present in the core 9-mer peptide IRGDEVRQI within the two HLA-DRB1*03:01 and HLA-DRB3*01.01 strong binding 15-mer peptides suggesting that RGD motif may be the potential immune epitope.

Accordingly, infected HLA-DRB1*03:01 or HLA-DRB3*01.01 positive individuals may develop high affinity anti-RGD motif antibodies that react with the RGD motif in the host proteins, like fibrinogen, thrombin or von Willebrand factor, affecting haemostasis or participating in autoimmune disorders.

Link | PDF (Frontiers in Immunology)

 

[SNT Gatchaman]

Hypothesis paper.

we postulate that at least some of pathological manifestations in COVID-19 are linked to the S protein integrin binding motifs.

Integrins are heterodimeric transmembrane glycoproteins composed of a and b subunits that bind extracellular matrix, cellsurface, and soluble ligands. They serve as cell adhesion receptors for numerous ligands playing an important role in signalling processes during infection and inflammation as well as in immunity, cell adhesion, cell migration, angiogenesis and carcinogenesis

The RGD (arginine/glycine/aspartic acid) amino acid sequence is the most frequent motif that plays a key role in integrin binding

the RGD motif in Epstein-Barr virus (EBV) protein BMRF-2 is critical in infection of oral epithelial cells with EBV upon binding to b1 integrin subunit

Furthermore, it is known that the RGD motif binding integrins play a significant role in coagulation, innate immunity, inflammation and autoimmunity. The RGD motif within plasma coagulation proteins such as fibrinogen, thrombin and von Willebrand factor (vWf) as well as within endothelial cell adhesion proteins fibronectin, laminin and vitronectin, binds to target integrins that are present on cells involved in coagulation, cell adhesion and/or immunity. The binding of fibrinogen to glycoprotein IIb/IIIa (GPIIb/IIIa), also known as platelet integrin aIIbb3, plays a central role in platelet activation, haemostasis and arterial thrombosis.

The recently evolved SARS CoV-2 S protein RGD motif (aa403-405) within the receptor binding domain (RBD) has been proposed to bind platelet integrin aIIbb3. The RGD motif is not present in the S proteins from any other known human or bat coronavirus

Besides fibrinogen, other acute phase proteins such as prothrombin and vWF are integrin aIIbb3 ligands, and they also use the RGD motif to bind activated platelets

Fibrinogen also binds to integrin a5b1 on endothelial cells via the carboxyl-terminal RGD sequence (aa572-574) of a-chain with high affinity (Kd = 65 nM), which have broad biological implications

Interestingly, Grobbelaar et al. have shown that the addition of S1 protein to platelet-poor plasma induces structural changes of fibrinogen b and g chains, complement C3, and thrombin as determined by mass spectrometry, which may cause dysregulation of the coagulation process and resistance to fibrinolysis in COVID-19 patients if it occurs in vivo.

The binding to target integrins may play an important role in coagulation (integrin aIIbb3-RGD motif), cell adhesion (integrin a5b1-RGD/LDI motif), and inflammation (integrin a4b1/VLA-4LDI motif) and induce deregulation of these processes or apoptosis (integrin avb3-ECD motif). The fact that SARS CoV-2 Omicron variants BA.2, BA.4 and BA.5 with D405N mutation are less pathogenic with predominantly mild symptoms, support our assumption that the RGD motif plays very significant role in COVID-19.