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The amino-terminal domain of Mycobacterium tuberculosis ClpB protein plays a crucial role in its substrate disaggregation activity

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Prajna Tripathi, Priyanka Parijat, Virendra Kumar Patel, Janendra K. Batra

Original languageEnglish
Pages (from-to)1669-1690
Number of pages22
JournalFEBS Open Bio
Issue number10
PublishedOct 2018

Bibliographical note

Funding Information: This work was supported by the core grants to the National Institute of Immunology, New Delhi, from the Department of Biotechnology, Govt. of India. We thank Dr Vinay K. Nandicoori, National Institute of Immunology, for his valuable suggestions to this study. We thank Dr Chhaya I. Raje, Department of Biotechnology, National Institute of Pharmaceutical Education and Research, Mohali, India for her generous gift of anti-Mtb GAPDH antibody. We thank Dr M. I. Hassan, Centre for Interdisciplinary Research in Basic Science, JMI, New Delhi, for his help in dynamic light scattering experiments. Publisher Copyright: © 2018 The Authors. Published by FEBS Press and John Wiley & Sons Ltd. Copyright: Copyright 2018 Elsevier B.V., All rights reserved.

King's Authors


Mycobacterium tuberculosis (Mtb) is known to persist in extremely hostile environments within host macrophages. The ability to withstand such proteotoxic stress comes from its highly conserved molecular chaperone machinery. ClpB, a unique member of the AAA+ family of chaperones, is responsible for resolving aggregates in Mtb and many other bacterial pathogens. Mtb produces two isoforms of ClpB, a full length and an N-terminally truncated form (ClpB∆N), with the latter arising from an internal translation initiation site. It is not clear why this internal start site is conserved and what role the N-terminal domain (NTD) of Mtb ClpB plays in its function. In the current study, we functionally characterized and compared the two isoforms of Mtb ClpB. We found the NTD to be dispensable for oligomerization, ATPase activity and prevention of aggregation activity of ClpB. Both ClpB and ClpB∆N were found to be capable of resolubilizing protein aggregates. However, the efficiency of ClpB∆N at resolubilizing higher order aggregates was significantly lower than that of ClpB. Further, ClpB∆N exhibited reduced affinity for substrates as compared to ClpB. We also demonstrated that the surface of the NTD of Mtb ClpB has a hydrophobic groove that contains four hydrophobic residues: L97, L101, F140 and V141. These residues act as initial contacts for the substrate and are crucial for stable interaction between ClpB and highly aggregated substrates.

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