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Deciphering Molecular Virulence Mechanism of Mycobacterium tuberculosis Dop isopeptidase Based on Its Sequence–Structure–Function Linkage

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Abstract

The pupylation pathway marks proteins for prokaryotic ubiquitin-like protein (Pup)-proteasomal degradation and survival strategy of mycobacteria inside of the host macrophages. Deamidase of Pup (Dop) plays a central role in the pupylation pathway. It is still a matter of investigation to know the function of Dop in virulence of mycobacterial lineage. Hence, the present study was intended to describe the sequence–structure–function–virulence link of Dop for understanding the molecular virulence mechanism of Mycobacterium tuberculosis H37Rv (Mtb). Phylogenetic analysis of this study indicated that Dop has extensively diverged across the proteasome-harboring bacteria. The functional part of Dop was converged across the pathogenic mycobacterial lineage. The genome-wide analysis pointed out that the pupylation gene locus was identical to each other, but its genome neighborhood differed from species to species. Molecular modeling and dynamic studies proved that the predicted structure of Mtb Dop was energetically stable and low conformational freedom. Moreover, evolutionary constraints in Mtb Dop were intensively analyzed for inferring its sequence–structure–function relationships for the full virulence of Mtb. It indicated that evolutionary optimization was extensively required to stabilize its local structural environment at the side chains of mutable residues. The sequence–structure–function–virulence link of Dop might have retained in Mtb by reordering hydrophobic and hydrogen bonding patterns in the local structural environment. Thus, the results of our study provide a quest to understand the molecular virulence and pathogenesis mechanisms of Mtb during the infection process.

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Acknowledgments

We thank all the family volunteers who participated in this study. We gratefully acknowledge colleagues at Bharathidasan University for helpful discussions and suggestions on developing the manuscript.

Funding

Authors would like to thank the Life Science Research Board-Defense Research and Development Organization (DLS/81/48222/LSRB-249/BTB/2012), New Delhi, India, for financial assistance.

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  1. R. Prathiviraj and P. Chellapandi have contributed equally to this work.

Authors and Affiliations

  1. Molecular Systems Engineering Lab, Department of Bioinformatics, School of Life Sciences, Bharathidasan University, Tiruchirappalli, Tamil Nadu, 620024, India

    R. Prathiviraj & P. Chellapandi

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PR performed the bioinformatics analyses of the study guided by CP. PR interpreted the data and wrote the manuscript. CP designed and coordinated the study. All authors read and approved the final manuscript.

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Correspondence to P. Chellapandi.

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Prathiviraj, R., Chellapandi, P. Deciphering Molecular Virulence Mechanism of Mycobacterium tuberculosis Dop isopeptidase Based on Its Sequence–Structure–Function Linkage. Protein J 39, 33–45 (2020). https://doi.org/10.1007/s10930-019-09876-x

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