- Email: [email protected]
The ABC(E1)s of Ribosome Recycling and Reinitiation
Molecular Cell
Previews RNF4; both have been implicated in DNA damage response (Hay, 2013). Wei et al. (2017) find that Rfp1/2-Slx8 promotes in vitro ubiquitination of a Top2 sumoylation mimetic construct in a manner stimulated by DNA and etoposide. In addition, slx8 mutants rescue several rrp2 defects, such as reduced chromosomal Top2 levels and etoposide sensitivity. These lines of evidence suggest that Rrp2 antagonizes the Slx8 STUbL functions. The next key question is how Rrp2 can antagonize Rfp1/2-Slx8 in protecting sumoylated Top2 from ubiquitination and degradation. Wei et al. (2017)’s data suggest two mechanisms. First, Rrp2 outcompetes Rfp1/2-Slx8 in binding to SUMO chains. Second, upon interaction with sumoylated Top2, Rrp2 uses its translocase activity to strip Top2 from DNA. Both mechanisms can reduce the chance of STUbL acting on sumoylated Top2. As such, Rrp2 has the upper hand in the battle over influencing the fate of sumoylated Top2 (Figure 1). Future investigation shall detail the interplay between these enzymes during the multiple steps of Top2 reaction as well as assess their importance in other Top2-mediated cellular processes. Are the uncovered Rrp2 functions conserved in other organisms? Wei et al. (2017) show that lacking the budding yeast Rrp2 homolog Uls1 also specifically
leads to Top2 poison sensitivity. In addition to and as seen for Rrp2, Uls1’s ability to cope with etoposide requires its translocase activity and SIMs. These findings suggest that this family of proteins use conserved functions to affect Top2 metabolism. Whether these functions also influence other sumoylated proteins will be interesting to consider. Despite the observed similarities, Uls1 and Rrp2 also have differences. Though both proteins contain RING domain indicative of ubiquitin ligase function (Cal-Bakowska et al., 2011), available data only support this function for Uls1 (Uzunova et al., 2007), but not Rrp2 (at least toward Top2). Whether Rrp2 can act as an ubiquitin ligase toward other proteins remains to be determined. The current study further suggests that the RING of Uls1, but not of Rrp2, is involved in coping with Top2 poison. Future examination of different features of Rrp2 and Uls1, as well as their relationships with other proteins that affect the metabolism of sumolyated proteins, such as the Slx8 STUbL, desumoylation enzymes, and segregases, can provide additional insights into protein dynamic regulation. As Top2 metabolism influences multiple forms of DNA transaction and has direct clinical implication, a new aspect of Top2 regulation by SUMO, ubiquitin, and DNA translocase, as revealed by
Wei et al. (2017), has enriched our understanding of Top2 control and may provide potential avenues to modulate Top2 poison effects in cancer treatment.
REFERENCES Cal-Bakowska, M., Litwin, I., Bocer, T., Wysocki, R., and Dziadkowiec, D. (2011). Nucleic Acids Res. 39, 8765–8777. Dziadkowiec, D., Petters, E., Dyjankiewicz, A., Karski, P., Garcia, V., Watson, A., and Carr, A.M. pin (2009). DNA Repair (Amst.) 8, 627–636. Flotho, A., and Melchior, F. (2013). Annu. Rev. Biochem. 82, 357–385. Hay, R.T. (2013). Biochem. Soc. Trans. 41, 463–473. Perry, J.J., Tainer, J.A., and Boddy, M.N. (2008). Trends Biochem. Sci. 33, 201–208. Shah, P.P., Zheng, X., Epshtein, A., Carey, J.N., Bishop, D.K., and Klein, H.L. (2010). Mol. Cell 39, 862–872. Uzunova, K., Go¨ttsche, K., Miteva, M., Weisshaar, S.R., Glanemann, C., Schnellhardt, M., Niessen, M., Scheel, H., Hofmann, K., Johnson, E.S., et al. (2007). J. Biol. Chem. 282, 34167–34175. Wei, Y., Diao, L.X., Lu, S., Wang, H.T., Suo, F., and Dong, M.Q. (2017). Mol. Cell 66, this issue, 581–596. Yan, H., Tammaro, M., and Liao, S. (2016). Genes (Basel) 7, E32. Zhang, Z., and Buchman, A.R. (1997). Mol. Cell. Biol. 17, 5461–5472.
The ABC(E1)s of Ribosome Recycling and Reinitiation Anthony P. Schuller1 and Rachel Green1,2,* 1Department
of Molecular Biology and Genetics Hughes Medical Institute Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA *Correspondence: [email protected] http://dx.doi.org/10.1016/j.molcel.2017.05.017 2Howard
In a recent issue of Nature Structural & Molecular Biology, Heuer et al. (2017) present a 3.9-A˚ cryo-EM structure of the 40S:ABCE1 post-splitting complex. This structure provides new insights into a dual role for ABCE1 in translation recycling and reinitiation and revisits the interpretation of Simonetti et al. (2016). Translation by the ribosome can be separated into four distinct stages: initiation, elongation, termination, and recycling.
In initiation, the coordinated actions of many factors (eIFs) lead to proper positioning of the 80S ribosome at the AUG
578 Molecular Cell 66, June 1, 2017 ª 2017 Elsevier Inc.
start codon with an initiator Met-tRNA bound and ready to go. During elongation, aminoacylated-tRNAs and elongation
Molecular Cell
Previews
Figure 1. Translation Cycle and the Multi-Faceted Role of ABCE1 ABCE1 stimulates peptidyl-tRNA hydrolysis by eRF1 to terminate translation. Subsequently, ABCE1 exerts mechanical force to split ribosomal subunits, remaining associated with the 40S subunit. This postsplitting complex then coordinates with initiation factors to begin a new round of translation.
factors (eEFs) promote the synthesis of the growing peptide chain until the ribosome reaches a termination codon. There, termination factors (eRFs) recognize stop codons and trigger hydrolysis of the nascent chain. And, during a final stage, terminated 80S ribosomes are recycled into 40S and 60S subunits. This final step is critical for maintaining ribosome homeostasis to permit subsequent rounds of initiation and thus the desired gene expression for the cell. At the heart of the termination and recycling processes is the ATP-binding cassette protein E1 (ABCE1 in mammals or Rli1 in S. cerevisiae). ABCE1 is an essential protein in eukaryotes, containing two nucleotide-binding domains (NBDs) and an N-terminal iron-sulfur (FeS) cluster domain. ABCE1 (or Rli1) was first shown to function in ribosome recycling by several groups (Barthelme et al., 2011; Pisarev et al., 2010; Shoemaker and Green, 2011) and has remained the focus of much ongoing work. ABCE1 functions
first to stimulate eRF1-mediated peptidyltRNA hydrolysis during termination (Shoemaker and Green, 2011) and subsequently functions to recycle ribosomal subunits using the force of ATP-binding and hydrolysis to dissociate the 60S and 40S subunits (Barthelme et al., 2011; Pisarev et al., 2010; Shoemaker and Green, 2011). Importantly, ABCE1 cooperates with the canonical termination factor eRF1 to promote each of these reactions. Critical support for these in vitro observations has come from ribosome profiling experiments in yeast (Young et al., 2015). In addition to this general role in recycling post-termination ribosome complexes, it is thought that ABCE1 works together with the eRF1 homolog PELOTA (Dom34 in yeast) to play a mechanistically similar role in rescuing ribosomes stalled on prob€renberg lematic mRNAs (reviewed in Nu and Tampe´, 2013). While the role of ABCE1 in ribosome recycling is clearly central to the cell, ABCE1 was initially implicated in transla-
tion initiation (Andersen and Leevers, 2007; Chen et al., 2006; Dong et al., 2004). In these studies, ABCE1 (or its orthologs Rli1 in S. cerevisiae and Pixie in D. melanogaster) were shown to coimmunoprecipitate with various components of the initiation complex machinery, including eIF2a, eIF2, eIF3, and eIF5. Rli1 and Pixie were also shown to interact with 40S ribosomal subunits in a sucrose gradient (Andersen and Leevers, 2007; Dong et al., 2004), and Pixie’s association was modulated by ATP hydrolysis (Andersen and Leevers, 2007). Finally, in yeast, Rli1 depletion resulted in impaired assembly of native preinitiation complexes and in overall reduced rates of bulk translation initiation, a functional consequence (Dong et al., 2004). As the events of initiation and recycling are effectively connected to one another in the translation cycle (Figure 1), it has remained plausible that ABCE1 might play a key role in promoting both events, for example, by first splitting the ribosomal subunits and then remaining attached to the small subunit to recruit initiation factors. In a recent issue of Nature Structural & Molecular Biology, Heuer et al. (2017) present a 3.9-A˚ cryo-EM structure of ABCE1 bound to the 40S ribosomal subunit that sheds light on a potential dual role of ABCE1 in subunit recycling and reinitiation. In order to capture this complex, the authors harnessed a ‘‘facilitated splitting’’ approach in vitro, incubating purified 80S ribosomes with ABCE1 and trapping the post-splitting, 40S-bound complex with the non-hydrolyzable ATP analog AMP-PNP. In their structure, ABCE1 is seen bound to the inter-subunit face of the 40S subunit, which is at the heart of ribosome function. The NBDs of ABCE1 bind to similar regions of 18S rRNA and ribosomal proteins, as observed previously in various 80S structures in the pre-splitting state (Becker et al., 2012; Brown et al., 2015; Preis et al., 2014), but here the ABCE1 NBDs are in a fully closed, nucleotide-occluded state. Moreover, a large conformational change of the ABCE1 FeS cluster toward the ribosomal A site and uS12 is observed, a change that must occur during ribosome splitting. Furthermore, the FeS cluster domain is rotated 150 relative to its pre-splitting state on the 80S ribosome. In this conformation, the FeS Molecular Cell 66, June 1, 2017 579
Molecular Cell
Previews cluster would directly clash with uL14 of the 60S subunit, thereby preventing 60S rejoining and naturally leading to initiation instead. This conformational change also has implications for the ribosome splitting mechanism: as the FeS cluster in the presplitting context makes contacts with the C-terminal domain of eRF1, it is easy to imagine that the energy created by the ABCE1 ‘‘power stroke’’ associated with ATP hydrolysis would push eRF1 into the inter-subunit space and thereby facilitate dissociation of the ribosomal subunits. The structure presented by Heuer et al. (2017) clarifies an earlier report published in Molecular Cell, Simonetti et al. (2016). This earlier work presented a moderateresolution (5.8-A˚) cryo-EM structure of a ‘‘48S initiation complex.’’ In this report, the authors isolated native complexes from rabbit reticulocyte lysates and assigned cryo-EM densities based on support from previous structural work as well as mass-spec analysis. While this study assigned density in the ribosome complex to eIF3i and g, Heuer et al. (2017) have made clear that the density reflected ABCE1 occupancy and highlights the dangers of assigning density in poorly resolved structures. Importantly, however,
580 Molecular Cell 66, June 1, 2017
if ABCE1 is readily isolated with native preinitiation complexes containing eIF2 and eIF3, this provides clear support for a role for ABCE1 in this stage of translation. The exciting structure by Heuer et al. provides insights into a multi-faceted role for ABCE1 in translation termination, recycling, and reinitiation (Figure 1). In such a model, ABCE1 functions first to stimulate translation termination and subsequently dissociates the 40S and 60S subunits in the recycling step, then remaining attached to the 40S subunit where it can interact with components of the initiation machinery to begin a new round of translation. Moving forward, it will be essential to understand the precise molecular mechanism that defines how the ATP-binding and hydrolysis cycles of ABCE1’s two nucleotide binding domains are coordinated in the processes of termination, recycling, and reinitiation.
Becker, T., Franckenberg, S., Wickles, S., Shoemaker, C.J., Anger, A.M., Armache, J.P., Sieber, H., Ungewickell, C., Berninghausen, O., Daberkow, I., et al. (2012). Nature 482, 501–506. Brown, A., Shao, S., Murray, J., Hegde, R.S., and Ramakrishnan, V. (2015). Nature 524, 493–496. Chen, Z.Q., Dong, J., Ishimura, A., Daar, I., Hinnebusch, A.G., and Dean, M. (2006). J. Biol. Chem. 281, 7452–7457. Dong, J., Lai, R., Nielsen, K., Fekete, C.A., Qiu, H., and Hinnebusch, A.G. (2004). J. Biol. Chem. 279, 42157–42168. Heuer, A., Gerovac, M., Schmidt, C., Trowitzsch, S., Preis, A., Ko¨tter, P., Berninghausen, O., Becker, T., Beckmann, R., and Tampe´, R. (2017). Nat. Struct. Mol. Biol. 24, 453–460. €renberg, E., and Tampe´, R. (2013). Trends BioNu chem. Sci. 38, 64–74. Pisarev, A.V., Skabkin, M.A., Pisareva, V.P., Skabkina, O.V., Rakotondrafara, A.M., Hentze, M.W., Hellen, C.U., and Pestova, T.V. (2010). Mol. Cell 37, 196–210. Preis, A., Heuer, A., Barrio-Garcia, C., Hauser, A., Eyler, D.E., Berninghausen, O., Green, R., Becker, T., and Beckmann, R. (2014). Cell Rep. 8, 59–65.
REFERENCES
Shoemaker, C.J., and Green, R. (2011). Proc. Natl. Acad. Sci. USA 108, E1392–E1398.
Andersen, D.S., and Leevers, S.J. (2007). J. Biol. Chem. 282, 14752–14760.
Simonetti, A., Brito Querido, J., Myasnikov, A.G., Mancera-Martinez, E., Renaud, A., Kuhn, L., and Hashem, Y. (2016). Mol. Cell 63, 206–217.
Barthelme, D., Dinkelaker, S., Albers, S.V., Londei, P., Ermler, U., and Tampe´, R. (2011). Proc. Natl. Acad. Sci. USA 108, 3228–3233.
Young, D.J., Guydosh, N.R., Zhang, F., Hinnebusch, A.G., and Green, R. (2015). Cell 162, 872–884.
Previews RNF4; both have been implicated in DNA damage response (Hay, 2013). Wei et al. (2017) find that Rfp1/2-Slx8 promotes in vitro ubiquitination of a Top2 sumoylation mimetic construct in a manner stimulated by DNA and etoposide. In addition, slx8 mutants rescue several rrp2 defects, such as reduced chromosomal Top2 levels and etoposide sensitivity. These lines of evidence suggest that Rrp2 antagonizes the Slx8 STUbL functions. The next key question is how Rrp2 can antagonize Rfp1/2-Slx8 in protecting sumoylated Top2 from ubiquitination and degradation. Wei et al. (2017)’s data suggest two mechanisms. First, Rrp2 outcompetes Rfp1/2-Slx8 in binding to SUMO chains. Second, upon interaction with sumoylated Top2, Rrp2 uses its translocase activity to strip Top2 from DNA. Both mechanisms can reduce the chance of STUbL acting on sumoylated Top2. As such, Rrp2 has the upper hand in the battle over influencing the fate of sumoylated Top2 (Figure 1). Future investigation shall detail the interplay between these enzymes during the multiple steps of Top2 reaction as well as assess their importance in other Top2-mediated cellular processes. Are the uncovered Rrp2 functions conserved in other organisms? Wei et al. (2017) show that lacking the budding yeast Rrp2 homolog Uls1 also specifically
leads to Top2 poison sensitivity. In addition to and as seen for Rrp2, Uls1’s ability to cope with etoposide requires its translocase activity and SIMs. These findings suggest that this family of proteins use conserved functions to affect Top2 metabolism. Whether these functions also influence other sumoylated proteins will be interesting to consider. Despite the observed similarities, Uls1 and Rrp2 also have differences. Though both proteins contain RING domain indicative of ubiquitin ligase function (Cal-Bakowska et al., 2011), available data only support this function for Uls1 (Uzunova et al., 2007), but not Rrp2 (at least toward Top2). Whether Rrp2 can act as an ubiquitin ligase toward other proteins remains to be determined. The current study further suggests that the RING of Uls1, but not of Rrp2, is involved in coping with Top2 poison. Future examination of different features of Rrp2 and Uls1, as well as their relationships with other proteins that affect the metabolism of sumolyated proteins, such as the Slx8 STUbL, desumoylation enzymes, and segregases, can provide additional insights into protein dynamic regulation. As Top2 metabolism influences multiple forms of DNA transaction and has direct clinical implication, a new aspect of Top2 regulation by SUMO, ubiquitin, and DNA translocase, as revealed by
Wei et al. (2017), has enriched our understanding of Top2 control and may provide potential avenues to modulate Top2 poison effects in cancer treatment.
REFERENCES Cal-Bakowska, M., Litwin, I., Bocer, T., Wysocki, R., and Dziadkowiec, D. (2011). Nucleic Acids Res. 39, 8765–8777. Dziadkowiec, D., Petters, E., Dyjankiewicz, A., Karski, P., Garcia, V., Watson, A., and Carr, A.M. pin (2009). DNA Repair (Amst.) 8, 627–636. Flotho, A., and Melchior, F. (2013). Annu. Rev. Biochem. 82, 357–385. Hay, R.T. (2013). Biochem. Soc. Trans. 41, 463–473. Perry, J.J., Tainer, J.A., and Boddy, M.N. (2008). Trends Biochem. Sci. 33, 201–208. Shah, P.P., Zheng, X., Epshtein, A., Carey, J.N., Bishop, D.K., and Klein, H.L. (2010). Mol. Cell 39, 862–872. Uzunova, K., Go¨ttsche, K., Miteva, M., Weisshaar, S.R., Glanemann, C., Schnellhardt, M., Niessen, M., Scheel, H., Hofmann, K., Johnson, E.S., et al. (2007). J. Biol. Chem. 282, 34167–34175. Wei, Y., Diao, L.X., Lu, S., Wang, H.T., Suo, F., and Dong, M.Q. (2017). Mol. Cell 66, this issue, 581–596. Yan, H., Tammaro, M., and Liao, S. (2016). Genes (Basel) 7, E32. Zhang, Z., and Buchman, A.R. (1997). Mol. Cell. Biol. 17, 5461–5472.
The ABC(E1)s of Ribosome Recycling and Reinitiation Anthony P. Schuller1 and Rachel Green1,2,* 1Department
of Molecular Biology and Genetics Hughes Medical Institute Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA *Correspondence: [email protected] http://dx.doi.org/10.1016/j.molcel.2017.05.017 2Howard
In a recent issue of Nature Structural & Molecular Biology, Heuer et al. (2017) present a 3.9-A˚ cryo-EM structure of the 40S:ABCE1 post-splitting complex. This structure provides new insights into a dual role for ABCE1 in translation recycling and reinitiation and revisits the interpretation of Simonetti et al. (2016). Translation by the ribosome can be separated into four distinct stages: initiation, elongation, termination, and recycling.
In initiation, the coordinated actions of many factors (eIFs) lead to proper positioning of the 80S ribosome at the AUG
578 Molecular Cell 66, June 1, 2017 ª 2017 Elsevier Inc.
start codon with an initiator Met-tRNA bound and ready to go. During elongation, aminoacylated-tRNAs and elongation
Molecular Cell
Previews
Figure 1. Translation Cycle and the Multi-Faceted Role of ABCE1 ABCE1 stimulates peptidyl-tRNA hydrolysis by eRF1 to terminate translation. Subsequently, ABCE1 exerts mechanical force to split ribosomal subunits, remaining associated with the 40S subunit. This postsplitting complex then coordinates with initiation factors to begin a new round of translation.
factors (eEFs) promote the synthesis of the growing peptide chain until the ribosome reaches a termination codon. There, termination factors (eRFs) recognize stop codons and trigger hydrolysis of the nascent chain. And, during a final stage, terminated 80S ribosomes are recycled into 40S and 60S subunits. This final step is critical for maintaining ribosome homeostasis to permit subsequent rounds of initiation and thus the desired gene expression for the cell. At the heart of the termination and recycling processes is the ATP-binding cassette protein E1 (ABCE1 in mammals or Rli1 in S. cerevisiae). ABCE1 is an essential protein in eukaryotes, containing two nucleotide-binding domains (NBDs) and an N-terminal iron-sulfur (FeS) cluster domain. ABCE1 (or Rli1) was first shown to function in ribosome recycling by several groups (Barthelme et al., 2011; Pisarev et al., 2010; Shoemaker and Green, 2011) and has remained the focus of much ongoing work. ABCE1 functions
first to stimulate eRF1-mediated peptidyltRNA hydrolysis during termination (Shoemaker and Green, 2011) and subsequently functions to recycle ribosomal subunits using the force of ATP-binding and hydrolysis to dissociate the 60S and 40S subunits (Barthelme et al., 2011; Pisarev et al., 2010; Shoemaker and Green, 2011). Importantly, ABCE1 cooperates with the canonical termination factor eRF1 to promote each of these reactions. Critical support for these in vitro observations has come from ribosome profiling experiments in yeast (Young et al., 2015). In addition to this general role in recycling post-termination ribosome complexes, it is thought that ABCE1 works together with the eRF1 homolog PELOTA (Dom34 in yeast) to play a mechanistically similar role in rescuing ribosomes stalled on prob€renberg lematic mRNAs (reviewed in Nu and Tampe´, 2013). While the role of ABCE1 in ribosome recycling is clearly central to the cell, ABCE1 was initially implicated in transla-
tion initiation (Andersen and Leevers, 2007; Chen et al., 2006; Dong et al., 2004). In these studies, ABCE1 (or its orthologs Rli1 in S. cerevisiae and Pixie in D. melanogaster) were shown to coimmunoprecipitate with various components of the initiation complex machinery, including eIF2a, eIF2, eIF3, and eIF5. Rli1 and Pixie were also shown to interact with 40S ribosomal subunits in a sucrose gradient (Andersen and Leevers, 2007; Dong et al., 2004), and Pixie’s association was modulated by ATP hydrolysis (Andersen and Leevers, 2007). Finally, in yeast, Rli1 depletion resulted in impaired assembly of native preinitiation complexes and in overall reduced rates of bulk translation initiation, a functional consequence (Dong et al., 2004). As the events of initiation and recycling are effectively connected to one another in the translation cycle (Figure 1), it has remained plausible that ABCE1 might play a key role in promoting both events, for example, by first splitting the ribosomal subunits and then remaining attached to the small subunit to recruit initiation factors. In a recent issue of Nature Structural & Molecular Biology, Heuer et al. (2017) present a 3.9-A˚ cryo-EM structure of ABCE1 bound to the 40S ribosomal subunit that sheds light on a potential dual role of ABCE1 in subunit recycling and reinitiation. In order to capture this complex, the authors harnessed a ‘‘facilitated splitting’’ approach in vitro, incubating purified 80S ribosomes with ABCE1 and trapping the post-splitting, 40S-bound complex with the non-hydrolyzable ATP analog AMP-PNP. In their structure, ABCE1 is seen bound to the inter-subunit face of the 40S subunit, which is at the heart of ribosome function. The NBDs of ABCE1 bind to similar regions of 18S rRNA and ribosomal proteins, as observed previously in various 80S structures in the pre-splitting state (Becker et al., 2012; Brown et al., 2015; Preis et al., 2014), but here the ABCE1 NBDs are in a fully closed, nucleotide-occluded state. Moreover, a large conformational change of the ABCE1 FeS cluster toward the ribosomal A site and uS12 is observed, a change that must occur during ribosome splitting. Furthermore, the FeS cluster domain is rotated 150 relative to its pre-splitting state on the 80S ribosome. In this conformation, the FeS Molecular Cell 66, June 1, 2017 579
Molecular Cell
Previews cluster would directly clash with uL14 of the 60S subunit, thereby preventing 60S rejoining and naturally leading to initiation instead. This conformational change also has implications for the ribosome splitting mechanism: as the FeS cluster in the presplitting context makes contacts with the C-terminal domain of eRF1, it is easy to imagine that the energy created by the ABCE1 ‘‘power stroke’’ associated with ATP hydrolysis would push eRF1 into the inter-subunit space and thereby facilitate dissociation of the ribosomal subunits. The structure presented by Heuer et al. (2017) clarifies an earlier report published in Molecular Cell, Simonetti et al. (2016). This earlier work presented a moderateresolution (5.8-A˚) cryo-EM structure of a ‘‘48S initiation complex.’’ In this report, the authors isolated native complexes from rabbit reticulocyte lysates and assigned cryo-EM densities based on support from previous structural work as well as mass-spec analysis. While this study assigned density in the ribosome complex to eIF3i and g, Heuer et al. (2017) have made clear that the density reflected ABCE1 occupancy and highlights the dangers of assigning density in poorly resolved structures. Importantly, however,
580 Molecular Cell 66, June 1, 2017
if ABCE1 is readily isolated with native preinitiation complexes containing eIF2 and eIF3, this provides clear support for a role for ABCE1 in this stage of translation. The exciting structure by Heuer et al. provides insights into a multi-faceted role for ABCE1 in translation termination, recycling, and reinitiation (Figure 1). In such a model, ABCE1 functions first to stimulate translation termination and subsequently dissociates the 40S and 60S subunits in the recycling step, then remaining attached to the 40S subunit where it can interact with components of the initiation machinery to begin a new round of translation. Moving forward, it will be essential to understand the precise molecular mechanism that defines how the ATP-binding and hydrolysis cycles of ABCE1’s two nucleotide binding domains are coordinated in the processes of termination, recycling, and reinitiation.
Becker, T., Franckenberg, S., Wickles, S., Shoemaker, C.J., Anger, A.M., Armache, J.P., Sieber, H., Ungewickell, C., Berninghausen, O., Daberkow, I., et al. (2012). Nature 482, 501–506. Brown, A., Shao, S., Murray, J., Hegde, R.S., and Ramakrishnan, V. (2015). Nature 524, 493–496. Chen, Z.Q., Dong, J., Ishimura, A., Daar, I., Hinnebusch, A.G., and Dean, M. (2006). J. Biol. Chem. 281, 7452–7457. Dong, J., Lai, R., Nielsen, K., Fekete, C.A., Qiu, H., and Hinnebusch, A.G. (2004). J. Biol. Chem. 279, 42157–42168. Heuer, A., Gerovac, M., Schmidt, C., Trowitzsch, S., Preis, A., Ko¨tter, P., Berninghausen, O., Becker, T., Beckmann, R., and Tampe´, R. (2017). Nat. Struct. Mol. Biol. 24, 453–460. €renberg, E., and Tampe´, R. (2013). Trends BioNu chem. Sci. 38, 64–74. Pisarev, A.V., Skabkin, M.A., Pisareva, V.P., Skabkina, O.V., Rakotondrafara, A.M., Hentze, M.W., Hellen, C.U., and Pestova, T.V. (2010). Mol. Cell 37, 196–210. Preis, A., Heuer, A., Barrio-Garcia, C., Hauser, A., Eyler, D.E., Berninghausen, O., Green, R., Becker, T., and Beckmann, R. (2014). Cell Rep. 8, 59–65.
REFERENCES
Shoemaker, C.J., and Green, R. (2011). Proc. Natl. Acad. Sci. USA 108, E1392–E1398.
Andersen, D.S., and Leevers, S.J. (2007). J. Biol. Chem. 282, 14752–14760.
Simonetti, A., Brito Querido, J., Myasnikov, A.G., Mancera-Martinez, E., Renaud, A., Kuhn, L., and Hashem, Y. (2016). Mol. Cell 63, 206–217.
Barthelme, D., Dinkelaker, S., Albers, S.V., Londei, P., Ermler, U., and Tampe´, R. (2011). Proc. Natl. Acad. Sci. USA 108, 3228–3233.
Young, D.J., Guydosh, N.R., Zhang, F., Hinnebusch, A.G., and Green, R. (2015). Cell 162, 872–884.