Intrinsically disordered regions (IDRs)-the proteome dark matter-confer dynamic adaptability upon rigid protein scaffolds. How IDRs and their adjacent folded domain (context) modulate enzyme substrate promiscuity and calibrate host-specific immune outputs remains unknown. Addressing this knowledge gap has substantial economic and industrial value in pharmaceutical drug discovery, biotechnological applications, and synthetic biology. Here, we report that the widely studied and conserved radical S-adenosylmethionine enzyme of intrinsic immunity, viperin, has a C-terminal IDR that calibrates synthesis of host-specific antiviral cocktails. We show that a C-terminal tripeptide and its context shape the IDR conformational space (ensemble), keeping active-site entry in a superposition of open and closed states. Consequently, transplanting the rat enzyme C-terminal tripeptide context into its human orthologue alters the antiviral cocktail output. These results revise the prevailing model that vertebrate viperins with identical active-site pockets generate the same antiviral output, establish a new framework in host-specific antiviral responses, and inform IDRs biotechnological applications.
Wu, M., Poire, D., Florance, H., Ciofi-Baffoni, S., James, W. S., Mroginski, M. A., Ebrahimi, K. H.
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