Hijacking of plasminogen by dengue virus: The kringle‐4 and ‐5 domains of plasminogen binds synergistically to the domain I of envelope protein

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Dengue fever is a serious health issue, particularly in tropical countries like Singapore. We have previously found that dengue virus (DENV) recruits human plasmin in blood meal to enhance the permeability of the mosquito midgut for infection. Here, using biolayer interferometry, we found that neither kringle-4 nor kringle-5 plasmin domains alone binds well to dengue virus. However, the domains together lead to a synergistic effect, with both kringle-4 and -5 domains required and sufficient for binding. Site-directed mutagenesis experiments showed that the N-terminal and C-terminal aspartic acid residues in the "DXD" acidic motifs of the kringle-4 and -5 domains likely have different roles when engaged with DENV. Hydrogen deuterium exchange mass spectrometry experiments on the plasmin:DENV complex led to the identification of two Lys-containing regions on domain I of the E-protein of DENV that are buried by plasmin and could be potential plasmin binding sites. These findings contradict with published literature that domain III of the DENV E-protein interacts with the kringle-1-3 domains of plasmin. We provide a plausible explanation for the observed discrepancies.

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