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Role of Pre-A motif in nitric oxide scavenging by truncated hemoglobin, HbN, of Mycobacterium tuberculosis.

DIR@IMTECH: CSIR-Institute of Microbial Technology

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Title Role of Pre-A motif in nitric oxide scavenging by truncated hemoglobin, HbN, of Mycobacterium tuberculosis.
 
Creator Lama, Amrita
Pawaria, Sudesh
Bidon-Chanal, Axel
Anand, Arvind
Gelpí, José Luis
Arya, Swati
Martí, Marcelo
Estrin, Dario A
Luque, F Javier
Dikshit, Kanak L
 
Subject QD Chemistry
 
Description Mycobacterium tuberculosis truncated hemoglobin, HbN, is endowed with a potent nitric-oxide dioxygenase activity and has been found to relieve nitrosative stress and enhance in vivo survival of a heterologous host, Salmonella enterica Typhimurium, within the macrophages. These findings implicate involvement of HbN in the defense of M. tuberculosis against nitrosative stress. The protein carries a tunnel system composed of a short and a long tunnel branch that has been proposed to facilitate diatomic ligand migration to the heme and an unusual Pre-A motif at the N terminus, which does not contribute significantly to the structural integrity of the protein, as it protrudes out of the compact globin fold. Strikingly, deletion of Pre-A region from the M. tuberculosis HbN drastically reduces its ability to scavenge nitric oxide (NO), whereas its insertion at the N terminus of Pre-A lacking HbN of Mycobacterium smegmatis improved its nitric-oxide dioxygenase activity. Titration of the oxygenated adduct of HbN and its mutants with NO indicated that the stoichiometric oxidation of protein is severalfold slower when the Pre-A region is deleted in HbN. Molecular dynamics simulations show that the excision of Pre-A motif results in distinct changes in the protein dynamics, which cause the gate of the tunnel long branch to be trapped into a closed conformation, thus impeding migration of diatomic ligands toward the heme active site. The present study, thus, unequivocally demonstrates vital function of Pre-A region in NO scavenging and unravels its unique role by which HbN might attain its efficient NO-detoxification ability.
 
Publisher ASBMB
 
Date 2009-05-22
 
Type Article
PeerReviewed
 
Format application/pdf
 
Identifier http://crdd.osdd.net/open/564/1/dikshit09.pdf
Lama, Amrita and Pawaria, Sudesh and Bidon-Chanal, Axel and Anand, Arvind and Gelpí, José Luis and Arya, Swati and Martí, Marcelo and Estrin, Dario A and Luque, F Javier and Dikshit, Kanak L (2009) Role of Pre-A motif in nitric oxide scavenging by truncated hemoglobin, HbN, of Mycobacterium tuberculosis. The Journal of biological chemistry, 284 (21). pp. 14457-68. ISSN 0021-9258
 
Relation http://www.jbc.org/content/284/21/14457.long
http://crdd.osdd.net/open/564/