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The uniqueness of subunit ? of mycobacterial F-ATP synthases: An evolutionary variant for niche adaptation.

ABSTRACT: The F1F0 -ATP (F-ATP) synthase is essential for growth of Mycobacterium tuberculosis, the causative agent of tuberculosis (TB). In addition to their synthase function most F-ATP synthases possess an ATP-hydrolase activity, which is coupled to proton-pumping activity. However, the mycobacterial enzyme lacks this reverse activity, but the reason for this deficiency is unclear. Here, we report that a Mycobacterium-specific, 36-amino acid long C-terminal domain in the nucleotide-binding subunit ? (Mt?) of F-ATP synthase suppresses its ATPase activity and determined the mechanism of suppression. First, we employed vesicles to show that in intact membrane-embedded mycobacterial F-ATP synthases deletion of the C-terminal domain enabled ATPase and proton-pumping activity. We then generated a heterologous F-ATP synthase model system, which demonstrated that transfer of the mycobacterial C-terminal domain to a standard F-ATP synthase ? subunit suppresses ATPase activity. Single-molecule rotation assays indicated that the introduction of this Mycobacterium-specific domain decreased the angular velocity of the power-stroke after ATP binding. Solution X-ray scattering data and NMR results revealed the solution shape of Mt? and the 3D structure of the subunit ? C-terminal peptide 521PDEHVEALDEDKLAKEAVKV540 of M. tubercolosis (Mt?(521-540)), respectively. Together with cross-linking studies, the solution structural data lead to a model, in which Mt?(521-540) comes in close proximity with subunit ? residues 104-109, whose interaction may influence the rotation of the camshaft-like subunit ?. Finally, we propose that the unique segment Mt?(514-549), which is accessible at the C terminus of mycobacterial subunit ?, is a promising drug epitope.

SUBMITTER: Ragunathan P

PROVIDER: S-EPMC5500794 | biostudies-literature | 2017 Jul

REPOSITORIES: biostudies-literature

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The uniqueness of subunit α of mycobacterial F-ATP synthases: An evolutionary variant for niche adaptation.

Ragunathan Priya P Sielaff Hendrik H Sundararaman Lavanya L Biuković Goran G Subramanian Manimekalai Malathy Sony MS Singh Dhirendra D Singh Dhirendra D Kundu Subhashri S Wohland Thorsten T Frasch Wayne W Dick Thomas T Grüber Gerhard G

The Journal of biological chemistry 20170511 27

The F1F0 -ATP (F-ATP) synthase is essential for growth of Mycobacterium tuberculosis, the causative agent of tuberculosis (TB). In addition to their synthase function most F-ATP synthases possess an ATP-hydrolase activity, which is coupled to proton-pumping activity. However, the mycobacterial enzyme lacks this reverse activity, but the reason for this deficiency is unclear. Here, we report that a Mycobacterium-specific, 36-amino acid long C-terminal domain in ...[more]

PMID: 28495884

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Dataset Information

The uniqueness of subunit ? of mycobacterial F-ATP synthases: An evolutionary variant for niche adaptation.

Publications

The uniqueness of subunit α of mycobacterial F-ATP synthases: An evolutionary variant for niche adaptation.

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