Identification of cryptic subunits from an apicomplexan ATP synthase

Identification of cryptic subunits from an apicomplexan ATP synthase

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Identification of cryptic subunits from an apicomplexan ATP synthase

eLife 2018;7:e38097 DOI: 10.7554/eLife.38097

The mitochondrial ATP synthase is a macromolecular motor that uses the proton gradient to generate ATP. Proper ATP synthase function requires a stator linking the catalytic and rotary portions of the complex.

Our findings highlight divergent features of the central metabolic machinery in apicomplexans, which may reveal new therapeutic opportunities.

The ATP synthase is a highly conserved protein complex found in the plasma membrane of bacteria, the inner membrane of mitochondria, and the thylakoid membrane of chloroplasts. The complex consists of two functionally distinct portions: the hydrophilic F₁ and the membrane-bound F_o (Walker, 2013). The mechanism of this molecular motor is best understood for the mitochondrial ATP synthases of yeast and mammals. Within their mitochondria, the proton gradient generated by the electron transport chain (ETC) drives the rotation of a ring of csubunits in F_o and of the attached central stalk within F₁. This rotation causes the conformational changes in the α and β subunits of F₁ that mediate catalysis of ATP from ADP and inorganic phosphate (P_i) (Jonckheere et al., 2012). The stator, also known as the lateral stalk, is an essential component of the ATP synthase because it counteracts the rotation of the α and β subunits, enabling ATP synthesis (Dickson et al., 2006). It is therefore surprising that despite general conservation of the central subunits, the lateral elements of protozoan ATP synthases are structurally diverse, and these organisms appear to lack homologs for the stator subunits of yeast and mammals (Lapaille et al., 2010).

The elegant rotary mechanism of the mitochondrial ATP synthase requires a stator to impart the conformational changes on F₁ that drive ATP catalysis. It has therefore been a long-standing conundrum that most apicomplexan genomes appear to code for only the core subunits of the ATP synthase but none of the stator subunits.

Our results reveal highly divergent aspects of the apicomplexan ATP synthase and demonstrate their importance for parasite viability.

Our work demonstrates that distant homology searches can complement the molecular characterization of protein complexes in apicomplexans as in other divergent eukaryotes.

Having provided strong evidence for the role of ICAP2 in the ATP synthase, more work will be needed to characterize the structure of the complex and understand how its unusual features mediate the specific adaptations of apicomplexan mitochondria.

The variable impact of the ATP synthase on the various stages of different apicomplexans may reflect the ability of these parasites to adapt to the changing environmental conditions they encounter across their life cycles.

To further understand the effects that lead to mitochondrial fragmentation, it will be interesting to compare uncoupling mutations, like ICAP2 loss, to disruption of the catalytic or proton-transporting functions of the T. gondii ATP synthase.

inhibiting oxidative phosphorylation at different steps is expected to have different consequences, which should be investigated further as we explore these pathways as therapeutic targets in apicomplexans.

Future studies into the structure and function of these divergent features will help us understand their contributions to apicomplexan adaptation. Unlike most organisms, all of the ATP synthase subunits are encoded in the nuclear genome, making T. gondii a highly tractable organism to study the evolution of this important protein complex.