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3.A.28. The AAA-ATPase, Bcs1 (Bcs1) Family

The mitochondrial AAA-ATPase, Bcs1, mediates topogenesis of the Rieske protein, Rip1, a component of respiratory chains in bacteria, mitochondria, and chloroplasts (Wagener et al. 2011). The oligomeric AAA-ATPase, Bcs1, is involved in export of the folded Fe-S domain of Rip1 across the inner membrane and insertion of its transmembrane segment into an assembly intermediate of the cytochrome bc1 complex. Structural elements in Rip1 are required for recognition and export by as well as ATP-dependent lateral release from the AAA-ATPase. In bacteria and chloroplasts, Rip1 uses the Tat machinery for topogenesis; however, mitochondria have lost this machinery during evolution, and a member of the AAA-ATPase family has taken over its function (Wagener et al., 2011).  Mutations in Bcs1 lead to different properties of the protein and different disease-related symptoms (Wagener and Neupert 2012).  A conserved α-helix in Bcs1 is required for Respiratory Complex III maturation (Sawamura et al. 2014). Human BCS1 has been implicated in human mitochondrial disorders (e.g. Björnstad and Gracile syndromes) (Ostojić et al. 2014). The outer membrane AAA-ATPase of Arabidopsis thaliana, AtOM66, affects cell death and pathogen resistance (Zhang et al. 2014). 

Kater et al. 2020 presented the structure of Saccharomyces cerevisiae Bcs1, an AAA-ATPase of the inner mitochondrial membrane. Bcs1 facilitates the translocation of the Rieske protein, Rip1, which requires folding and incorporation of a 2Fe-2S cluster before translocation and subsequent integration into the bc1 complex (TC# 3.D.3). Bcs1 assembles into an exclusively heptameric homo-oligomer, with each protomer consisting of an amphipathic transmembrane helix, a middle domain and an ATPase domain. Together they form two aqueous vestibules, the first being accessible from the mitochondrial matrix and the second positioned in the inner membrane, with both separated by the seal-forming middle domain. On the basis of this unique architecture, Kater et al. 2020 proposed an airlock-like translocation mechanism for folded Rip1.

Bcs1, a homo-heptameric transmembrane AAA-ATPase, facilitates folded Rieske iron-sulfur protein translocation across the inner mitochondrial membrane. Structures in different nucleotide states (ATPgammaS, ADP, apo) provide conformational snapshots of the enzyme. Using high-speed atomic force microscopy (HS-AFM) and line scanning (HS-AFM-LS), Pan et al. 2023 characterized single-molecule Bcs1 ATPase cycling. While the ATP conformation had an ~5600 ms lifetime, independent of the ATP-concentration, the ADP/apo conformation lifetime was ATP-concentration dependent and reached ~320 ms at a saturating ATP-concentration, giving a maximal turnover rate of 0.17 per second. Bcs1 ATPase cycle conformational changes occurr in concert. Pan et al. 2023 proposed that the transport mechanism involves opening the IMS gate through energetically costly straightening of the transmembrane helices, potentially driving rapid gate resealing. These results establish a concerted ATPase cycle mechanism in Bcs1, distinct from other AAA-ATPases that use a hand-over-hand mechanism.

This family belongs to the: AAA-ATPase Superfamily.

References associated with 3.A.28 family:

Kater, L., N. Wagener, O. Berninghausen, T. Becker, W. Neupert, and R. Beckmann. (2020). Structure of the Bcs1 AAA-ATPase suggests an airlock-like translocation mechanism for folded proteins. Nat Struct Mol Biol 27: 142-149. 31988523
Ostojić, J., J.P. Rago, and G. Dujardin. (2014). A novel mechanism involved in the coupling of mitochondrial biogenesis to oxidative phosphorylation. Microb Cell 1: 43-44. 28357209
Pan, Y., J. Zhan, Y. Jiang, D. Xia, and S. Scheuring. (2023). A concerted ATPase cycle of the protein transporter AAA-ATPase Bcs1. Nat Commun 14: 6369. 37821516
Sawamura, R., T. Ogura, and M. Esaki. (2014). A conserved α helix of Bcs1, a mitochondrial AAA chaperone, is required for the Respiratory Complex III maturation. Biochem. Biophys. Res. Commun. 443: 997-1002. 24361883
Tamai, S., H. Iida, S. Yokota, T. Sayano, S. Kiguchiya, N. Ishihara, J. Hayashi, K. Mihara, and T. Oka. (2008). Characterization of the mitochondrial protein LETM1, which maintains the mitochondrial tubular shapes and interacts with the AAA-ATPase BCS1L. J Cell Sci 121: 2588-2600. 18628306
Wagener, N. and W. Neupert. (2012). Bcs1, a AAA protein of the mitochondria with a role in the biogenesis of the respiratory chain. J Struct Biol 179: 121-125. 22575765
Wagener, N., M. Ackermann, S. Funes, and W. Neupert. (2011). A pathway of protein translocation in mitochondria mediated by the AAA-ATPase Bcs1. Mol. Cell 44: 191-202. 22017868
Zhang, B., O. Van Aken, L. Thatcher, I. De Clercq, O. Duncan, S.R. Law, M.W. Murcha, M. van der Merwe, H.S. Seifi, C. Carrie, C. Cazzonelli, J. Radomiljac, M. Höfte, K.B. Singh, F. Van Breusegem, and J. Whelan. (2014). The mitochondrial outer membrane AAA ATPase AtOM66 affects cell death and pathogen resistance in Arabidopsis thaliana. Plant J. 80: 709-727. 25227923