The kinetics of nsp7-11 polyprotein processing and impact on complexation with nsp16 among human coronaviruses

Kira Schamoni-Kast, Boris Krichel, Tomislav Damjanović, Fatema-Aqila Said, Thomas Kierspel, Sibel Toker and Charlotte Uetrecht ()
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Kira Schamoni-Kast: University of Lübeck
Boris Krichel: University of Lübeck
Tomislav Damjanović: University of Lübeck
Fatema-Aqila Said: University of Lübeck
Thomas Kierspel: University of Lübeck
Sibel Toker: University of Lübeck
Charlotte Uetrecht: University of Lübeck

Nature Communications, 2025, vol. 16, issue 1, 1-15

Abstract: Abstract In coronavirus (CoV) infection, polyproteins (pp1a/pp1ab) are processed into non-structural proteins (nsps), which largely form the replication/transcription complex (RTC). The polyprotein processing and complex formation is critical and offers potential therapeutic targets. However, the interplay of polyprotein processing and RTC-assembly remains poorly understood. Here, we study two key aspects: The order of polyprotein processing by viral main protease Mpro and its influence on complex formation with the methyltransferase nsp16. Moreover, we establish an approach to determine rate constants k from cleavage sites in structured CoV polyprotein based on native mass spectrometry (MS). The high sensitivity and precision of our method allow quantification of multi-reaction kinetics of nsp7-11 processing from four human pathogenic CoV species. The experimentally determined rate constants are put into perspective with a comprehensive analysis of primary sequences and structural models, revealing distinct cleavage mechanisms for each site based on their local structural environments. Our systematic approach provides a blueprint for kinetic analysis of complex multi-cleavage reactions.

Date: 2025
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DOI: 10.1038/s41467-025-61554-y

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