Coevolved Positions Represent Key Functional Properties in the Trypsin-Like Serine Proteases Protein Family

Abstract

Trypsin-like serine proteases are a group of homologous enzymes which exert multiple roles in both vertebrate and invertebrate organisms. Key properties of these enzymes include their activation from an inactive zymogen form to their active form by cleavage of residues in their N-terminus, the presence of a conserved catalytic triad of residues, and the existence of different patterns of substrate selectivity for residue cleavage between the various members of this protein family. In this article, we apply the decomposition of residue coevolution networks computational method to find sets of residues related to some of these key properties, especially to zymogen activation. Positive selection detection, normal modes analysis, and the calculation of thermal couplings between the bovine trypsinogen and bovine trypsin structures residues yielded further information for understanding the zymogen activation process and highlighted the importance of some of the coevolved set residues during these transitions.

Characterization of an Allosteric Pocket in Zika Virus NS2B-NS3 Protease

“…Such sets commonly map to functionally relevant sites, and, when they are not highly conserved in the protein family, can be related to determinants of class-specific features. In a previous study involving serine proteases, a large set of conserved and coevolving residues groups the catalytic triad and other residues around the active site, while smaller and less conserved sets are related to class-related features such as the specific pocket in trypsins . Flaviviral proteases present a large set of 16 coevolving and conserved residues, present in all NS3 from major pathogens, among which five (Gln96, Pro113, Asn152, Gln110, and Gly114) are in the NS2B-NS3 interface, and four are around Ala125 (Pro113, Gly124, Ser163, and Gly114).…”

“…In a previous study involving serine proteases, a large set of conserved and coevolving residues groups the catalytic triad and other residues around the active site, while smaller and less conserved sets are related to class-related features such as the specific pocket in trypsins. 39 Flaviviral proteases present a large set of 16 coevolving and conserved residues, 38 present in all NS3 from major pathogens, among which five (Gln96, Pro113, Asn152, Gln110, and Gly114) are in the NS2B-NS3 interface, and four are around Ala125 (Pro113, Gly124, Ser163, and Gly114). A second coevolving set, present in the NS3 proteases from Zika, dengue, yellow fever, West Nile fever, Japanese encephalitis, and St. Louis encephalitis virus, but absent on the tick-borne encephalitis, looping ill, and tickborne Powassan virus, contains six residues, Leu65, Val100, Asn108, Leu98, Phe116, and Thr111, which are in the NS2B-NS3 interface, Phe116 being close to Ala125.…”

An ancient enzyme finds a new home: Prevalence and neofunctionalization of trypsin in marine phytoplankton

“…Trypsin represents a conserved family of enzymes occurring in organisms ranging from bacteria to mammals 2,3 . It is believed to be absent in plants and protists 4,5 . Indeed, many animal trypsin genes have extremely well-understood physiological roles, to digest protein food and to activate zymogen, an activator of other proteases 6,7 , etc..…”

“…2003), it has been believed to be absent in plants and protists (Rojas and Doolittle 2002, Querino Lima Afonso et al. 2020). According to the MEROPS nomenclature, there are 109 S1A serine proteases with species identification and annotated as trypsin enzymes, all of which are exclusively from animals.…”

Outlook on the Development and Application of Molecular Simulations in Latin America

“…MD simulations proved to be one of the most popular computational chemistry tools. In this special issue, atomistic MD simulations have been applied in many studies to understand key structural and functional properties of proteins, − receptor activation, insights into the binding of ligands, − mutations, ,− protein folding, and inhibitor design . In addition, combined free energy simulations and NMR chemical-shift perturbation has been utilized to identify transient cation-π contacts in proteins .…”