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Control of rotation of the F1FO-ATP synthase nanomotor by an inhibitory α-helix from unfolded ε or intrinsically disordered ζ and IF1 proteins

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Abstract

The ATP synthase is a ubiquitous nanomotor that fuels life by the synthesis of the chemical energy of ATP. In order to synthesize ATP, this enzyme is capable of rotating its central rotor in a reversible manner. In the clockwise (CW) direction, it functions as ATP synthase, while in counter clockwise (CCW) sense it functions as an proton pumping ATPase. In bacteria and mitochondria, there are two known canonical natural inhibitor proteins, namely the ε and IF1 subunits. These proteins regulate the CCW F1FO-ATPase activity by blocking γ subunit rotation at the αDP/βDP/γ subunit interface in the F1 domain. Recently, we discovered a unique natural F1-ATPase inhibitor in Paracoccus denitrificans and related α-proteobacteria denoted the ζ subunit. Here, we compare the functional and structural mechanisms of ε, IF1, and ζ, and using the current data in the field, it is evident that all three regulatory proteins interact with the αDP/βDP/γ interface of the F1-ATPase. In order to exert inhibition, IF1 and ζ contain an intrinsically disordered N-terminal protein region (IDPr) that folds into an α-helix when inserted in the αDP/βDP/γ interface. In this context, we revised here the mechanism and role of the ζ subunit as a unidirectional F-ATPase inhibitor blocking exclusively the CCW F1FO-ATPase rotation, without affecting the CW-F1FO-ATP synthase turnover. In summary, the ζ subunit has a mode of action similar to mitochondrial IF1, but in α-proteobacteria. The structural and functional implications of these intrinsically disordered ζ and IF1 inhibitors are discussed to shed light on the control mechanisms of the ATP synthase nanomotor from an evolutionary perspective.

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Fig. 1: Structures of the F1FO-ATPsynthase from E. coli, P. denitrificans, and S. cerevisiae
Fig. 2: Representation of the F1FO-ATPsynthase from bacteria
Fig. 3: Model of the ATP synthesis binding change mechanism
Fig. 4: Model of the ATP hydrolysis binding change mechanism for the bacterial F1-ATPase
Fig. 5: Model of the ATP hydrolysis binding change mechanism for the human F1-ATPase
Fig. 6: Conformational changes of the bacterial ε subunit during active to inactive F1-ATPase transitions
Fig. 7: Loss of ATP binding site of the ε subunit from bacteria belonging to the α-proteobacteria class
Fig. 8: Conformational change of the mitochondrial IF1 from short N-terminal α-helix to extended N-terminal inhibitory α-helix
Fig. 9: Conformational change of the ζ subunit of Paracoccus denitrificans F1-ATPase from N-terminal disordered to inhibitory ordered α-helical structure
Fig. 10: The consensus INGECORE residues of the αDPβDPγ interface form part of the binding site of the inhibitory N-terminus of the ζ subunit in Paracoccus denitrificans
Fig. 11: Unidirectional pawl-ratchet mechanism of the ζ subunit of the ATP synthase of Paracoccus denitrificans

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Acknowledgements

This work was supported by grants from México, (CONACyT) Grant CB-2011-01-167622 and U.N.A.M. (DGAPA) Grant PAPIIT- IN221216 (both to J. J. G.-T.). This work is part of PhD Thesis of FMH at the “Programa de Maestría y Doctorado en Ciencias Bioquímicas de la Universidad Nacional Autónoma de México (U.N.A.M.), with JJGT as PhD advisor. FMH was supported by CONACyT Ph.D. Fellowship 277245, and MZZ by CONACyT Fund I0010, Fellowship No. 277592. The kind help to improve the main text of this review paper is gratefully acknowledged to Pattie Nelson, Oregon, and to Prof. Duncan McMillan, Delft. The ζ knockout mutant of P. denitrificans was constructed in collaboration with Prof. Miguel Angel Cevallos from UNAM.

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  1. Departamento de Biología, Facultad de Química, Ciudad Universitaria, Universidad Nacional Autónoma de México (U.N.A.M.), Circuito Escolar s/n. Laboratorio 203, Edificio “F”., Delegación Coyoacán, 04510, Mexico City, CP, Mexico

    Francisco Mendoza-Hoffmann, Raquel Ortega & José J. García-Trejo

  2. Department of Applied Chemistry, Graduate School of Engineering, The University of Tokyo, Tokyo, 113-8656, Japan

    Mariel Zarco-Zavala

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  1. Francisco Mendoza-Hoffmann
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  2. Mariel Zarco-Zavala
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  3. Raquel Ortega
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  4. José J. García-Trejo
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Correspondence to José J. García-Trejo.

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Mendoza-Hoffmann, F., Zarco-Zavala, M., Ortega, R. et al. Control of rotation of the F1FO-ATP synthase nanomotor by an inhibitory α-helix from unfolded ε or intrinsically disordered ζ and IF1 proteins. J Bioenerg Biomembr 50, 403–424 (2018). https://doi.org/10.1007/s10863-018-9773-9

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