Abstract
Mycobacterium tuberculosis infection remains a major threat to human health worldwide. Drug treatments against tuberculosis (TB) induce expression of several mycobacterial proteins, including IniA, but its structure and function remain poorly understood. Here, we report the structures of Mycobacterium smegmatis IniA in both the nucleotide-free and GTP-bound states. The structures reveal that IniA folds as a bacterial dynamin-like protein (BDLP) with a canonical GTPase domain followed by two helix-bundles (HBs), named Neck and Trunk. The distal end of its Trunk domain exists as a lipid-interacting (LI) loop, which binds to negatively charged lipids for membrane attachment. IniA does not form detectable nucleotide-dependent dimers in solution. However, lipid tethering indicates nucleotide-independent association of IniA on the membrane. IniA also deforms membranes and exhibits GTP-hydrolyzing dependent membrane fission. These results confirm the membrane remodeling activity of BDLP and suggest that IniA mediates TB drug-resistance through fission activity to maintain plasma membrane integrity.
Highlights
Mycobacterium tuberculosis infection remains a major threat to human health worldwide
IniA mediates drug tolerance[7], tandem bacterial dynamin-like protein (BDLP) DynA and DynB in the filamentous bacteria Streptomyces play a role in cytokinesis during sporulation[8,10], and LeoA in enterotoxigenic Escherichia coli (E. coli) strain H10407 is proposed to be linked to toxin secretion[11,12]
The HB1/Neck is formed by four helices: α(−1) and α0 are N-terminal extensions of the GTPase domain, α6b follows α6a which is the last helix of the GTPase domain, and α11b is the last helix of the polypeptide
Summary
Mycobacterium tuberculosis infection remains a major threat to human health worldwide. IniA and iniC both encode GTPase domain containing proteins predicted to be homologs of bacterial dynamin-like protein (BDLP) and, members of the dynamin superfamily[8,9] Functional investigation of these BDLPs would provide critical insight into mycobacterial adaption upon drug treatment and subsequently offer new clues toward optimization of antibiotic strategies. Our results suggested that IniA, like other BDLPs, has weak GTPase activity and nucleotidedependent dimerization in solution, but tends to form nucleotideindependent homotypic interactions on the membrane and cuts the membrane. These features are linked to IniA-mediated isoniazid resistance
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
