Redox-Active Conopeptide Li520 Has Evolved to Catalyze Oxidative Folding of Conotoxins.
| Autor: | Dhannura S; Department of Chemistry, School of Chemical Sciences, Central University of Karnataka, Kalaburagi 585367, Karnataka, India., Shekh S; Department of Chemistry, School of Chemical Sciences, Central University of Karnataka, Kalaburagi 585367, Karnataka, India., Dhurjad P; Department of Pharmaceutical Analysis, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad 500037, Telangana, India., Dolle A; Department of Chemistry, School of Chemical Sciences, Central University of Karnataka, Kalaburagi 585367, Karnataka, India., Kakkat S; Department of Chemistry, School of Chemical Sciences, Central University of Karnataka, Kalaburagi 585367, Karnataka, India., Vishwajyothi; Department of Chemistry, School of Chemical Sciences, Central University of Karnataka, Kalaburagi 585367, Karnataka, India., Vijayasarathy M; National Centre for Biological Sciences (NCBS), Bangalore 560065, India., Sonti R; Department of Pharmaceutical Analysis, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad 500037, Telangana, India., Gowd KH; Department of Chemistry, School of Chemical Sciences, Central University of Karnataka, Kalaburagi 585367, Karnataka, India. |
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| Jazyk: | angličtina |
| Zdroj: | ACS omega [ACS Omega] 2024 Aug 28; Vol. 9 (36), pp. 37596-37609. Date of Electronic Publication: 2024 Aug 28 (Print Publication: 2024). |
| DOI: | 10.1021/acsomega.4c01028 |
| Abstrakt: | The evolution of miniature conopeptide Li520 (COWC*, *: C-terminal amidation) to exhibit the disulfide isomerase activity was probed using structure, function, disulfide conformation, and the precursor gene sequence. The peptides Li520, Li504, [O2A]Li520, [W3A]Li520, and Grx506, homologues active-site motif of glutaredoxin, were chemically synthesized and assessed for their disulfide reduction potential, intrinsic folding of disulfides, and disulfide isomerization activity on α-conotoxin ImI. The reduction potential of the disulfide of peptides varies from -189 to -344 mV, which is within the range observed for the redox family of proteins that modulates the folding of protein disulfides. The oxidative folding studies confirm the significance of the tryptophan residue in engaging Li520 in disulfide-exchange reactions and the role of proline hydroxylation in extending the lifetime of Li520 in a reduced free thiol state. Studies of quenching of tryptophan fluorescence by the disulfide in situ folding reaction in conjunction with the optimized structures by density functional theory (DFT) confirm the difference in conformation of disulfides between the native and mutant peptides. Interestingly, the native peptide Li520/Li504 shares a similar disulfide conformation of (-,-)AntiRHHook with the redox family of proteins known to modulate disulfides, particularly in lieu of the tetrapeptide of glutaredoxin, deviating from its disulfide conformation compared to its naive protein. Analysis of the precursor gene sequences of M-superfamily conotoxins revealed the presence of Li520 in different cone snail species with distinct food habits and possible modes of evolution through the diversification of cysteine motifs. The results of the report suggest that the short redox conopeptide Li520 has evolved to facilitate the oxidative folding of conotoxins and may be useful to develop as reagents for the synthesis of therapeutically important cysteine-rich peptides. Competing Interests: The authors declare no competing financial interest. (© 2024 The Authors. Published by American Chemical Society.) |
| Databáze: | MEDLINE |
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