While precise mechanisms underlying cardiovascular diseases (CVDs) are still not fully\nunderstood, previous studies suggest that the innate immune system, through Toll-like receptor 4\n(TLR4), plays a crucial part in the pathways leading to these diseases, mainly because of its interplay\nwith endogenous molecules. The Heat-shock protein 70 family (HSP70-70kDa) is of particular interest\nin cardiovascular tissues as it may have dual effects when interacting with TLR4 pathways. Although\nthe hypothesis of the HSP70 family members acting as TLR4 ligands is becoming widely accepted,\nto date no co-crystal structure of this complex is available and it is still unknown whether this process\nrequires the co-adaptor MD2. In this study, we aimed at investigating the interplay between the\nTLR4/MD2 complex and HSP70 family members in the human cardiovascular system through\ntranscriptomic data analysis and at proposing a putative interaction model between these proteins.\nWe report compelling evidence of correlated expression levels between TLR4 and MD2 with HSP70\ncognate family members, especially in heart tissue. In our molecular docking simulations, we found\nthat HSP70 in the ATP-bound state presents a better docking score towards the TLR4/MD2 complex\ncompared to the ADP-bound state (-22.60 vs. -10.29 kcal/mol, respectively). Additionally, we show\nvia a proximity ligation assay for HSP70 and TLR4, that cells stimulated with ATP have higher\nformation of fluorescent spots and that MD2 might be required for the complexation of these proteins.\nThe insights provided by our computational approach are potential scaffolds for future in vivo studies\ninvestigating the interplay between the TLR4/MD2 complex and HSP70 family members in the\ncardiovascular system.
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