Characterization of cysteine thiol modifications based on protein microenvironments and local secondary structures. Issue 2 (29th November 2017)

• Record Type: Journal Article
• Authors: Bhatnagar, Akshay; Bandyopadhyay, Debashree
• Is Part Of: Proteins. Volume 86:Issue 2(2018)
• Page Start: 192
• Page End: 209
• Publication Date: 2017-11-29
• Subjects: cysteine redox -- cysteine thiol pKa -- glutathionylation -- metalloenzymes -- nitrosylation -- protein microenvironment -- reactive nitrogen species (RNS) -- reactive oxygen species (ROS) -- ribosylation -- selenylation; Proteins -- Periodicals; Proteins -- Periodicals; 572.6
• DOI: 10.1002/prot.25424
• Languages: English
• ISSNs: 0887-3585

Abstract

Abstract: We have demonstrated earlier that protein microenvironments were conserved around disulfide‐bridged cystine motifs with similar functions, irrespective of diversity in protein sequences. Here, cysteine thiol modifications were characterized based on protein microenvironments, secondary structures and specific protein functions. Protein microenvironment around an amino acid was defined as the summation of hydrophobic contributions from the surrounding protein fragments and the solvent molecules present within its first contact shell. Cysteine functions (modifications) were grouped into enzymatic and non‐enzymatic classes. Modifications studied were—disulfide formation, thio‐ether formation, metal‐binding, nitrosylation, acylation, selenylation, glutathionylation, sulfenylation, and ribosylation. 1079 enzymatic proteins were reported from high‐resolution crystal structures. Protein microenvironments around cysteine thiol, derived from above crystal structures, were clustered into 3 groups—buried‐hydrophobic, intermediate and exposed‐hydrophilic clusters. Characterization of cysteine functions were statistically meaningful for 4 modifications (disulfide formation, thioether formation, sulfenylation, and iron/zinc binding) those have sufficient amount of data in the current dataset. Results showed that protein microenvironment, secondary structure and protein functions were conserved for enzymatic cysteine functions, in contrast to the same function from non‐enzymatic cysteines. Disulfide forming enzymatic cysteines were tightly packed within intermediate protein microenvironment cluster, have alpha‐helical conformation and mostly belonged to CxxC motif of electron transport proteins. Disulfide forming non‐enzymatic cysteines did not belong to conserved motif and have variable secondary structures. Similarly, enzymatic thioether forming cysteines have conserved microenvironment compared to non‐enzymatic cystienes. Based on the compatibility between protein microenvironment and cysteine modifications, more efficient drug molecules could be designed against cysteine‐related diseases.