Saliva of blood-feeding arthropods carries several antihemostatic compounds whose physiological role is to facilitate successful acquisition of blood. The identification of novel natural anticoagulants and the understanding of their mechanism of action may offer opportunities for designing new antithrombotics disrupting blood clotting. We report here an in depth structural and functional analysis of the anophelin family member cE5, a salivary protein from the major African malaria vector Anopheles gambiae that specifically tightly and quickly binds and inhibitss thrombin. Using calorimetry, functional assays and complementary structural techniques we show that the central region of the protein, encompassing amino acids Asp31-Arg62, is the region mainly responsible for α-thrombin binding and inhibition. As previously reported for the Anopheles albimanus orthologue anophelin, cE5 binds both thrombin exosite I with segment Glu35-Asp47 and the catalytic site with the region Pro49-Arg56, which includes the highly conserved DPGR tetrapeptide. Moreover, the N-terminal Ala1-Ser30 region of cE5 (which includes an RGD tripeptide) and the additional C-terminal serine-rich Asn63-Glu82 region (absent in orthologues from anophelines of the New World species A. albimanus and .darlingi) also played some functionally relevant role. Indeed, we observed decreased thrombin binding and inhibitory properties even when using the central cE5 fragment (Asp31-Arg62) alone. In summary, these results shed additional light on the mechanism of thrombin binding and inhibition by this family of salivary anticoagulants from anopheline mosquitoes.
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