Allosteric control of dynamin-related protein 1-catalyzed mitochondrial fission through a conserved disordered C-terminal Short Linear Motif

Isabel Pérez-Jover; Kristy Rochon; Di Hu; Pooja Madan Mohan; Isaac Santos-Perez; Julene Ormaetxea Gisasola; Juan Manuel Martinez Galvez; Jon Agirre; Xin Qi; Jason A Mears; Anna V Shnyrova; Rajesh Ramachandran

doi:10.21203/rs.3.rs-3161608/v1

Allosteric control of dynamin-related protein 1-catalyzed mitochondrial fission through a conserved disordered C-terminal Short Linear Motif

Isabel Pérez-Jover, Kristy Rochon, Di Hu, Pooja Madan Mohan, Isaac Santos-Perez, Julene Ormaetxea Gisasola, Juan Manuel Martinez Galvez, Jon Agirre, Xin Qi, Jason A Mears, Anna V Shnyrova, Rajesh Ramachandran

Chemistry

Research output: Working paper › Preprint

Abstract

The mechanochemical GTPase dynamin-related protein 1 (Drp1) catalyzes mitochondrial fission, but the regulatory mechanisms remain ambiguous. Here we found that a conserved, intrinsically disordered, six-residue S hort Li near M otif at the extreme Drp1 C-terminus, named CT-SLiM, constitutes a critical allosteric site that controls Drp1 structure and function in vitro and in vivo . Extension of the CT-SLiM by non-native residues, or its interaction with the protein partner GIPC-1, constrains Drp1 subunit conformational dynamics, alters self-assembly properties, and limits cooperative GTP hydrolysis, leading to the fission of model membranes in vitro . In vivo , the availability of the native CT-SLiM is a requirement for productive mitochondrial fission, as both non-native extension and deletion of the CT-SLiM severely impair its progression. Thus, contrary to prevailing models, Drp1-catalyzed mitochondrial fission relies on allosteric communication mediated by the CT-SLiM, deceleration of GTPase activity, and coupled changes in subunit architecture and assembly-disassembly dynamics.

Original language	English
Publisher	Research Square
DOIs	https://doi.org/10.21203/rs.3.rs-3161608/v1
Publication status	Published - 13 Jul 2023

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Pérez-Jover, I., Rochon, K., Hu, D., Mohan, P. M., Santos-Perez, I., Gisasola, J. O., Galvez, J. M. M., Agirre, J., Qi, X., Mears, J. A., Shnyrova, A. V., & Ramachandran, R. (2023). Allosteric control of dynamin-related protein 1-catalyzed mitochondrial fission through a conserved disordered C-terminal Short Linear Motif. Research Square. https://doi.org/10.21203/rs.3.rs-3161608/v1

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title = "Allosteric control of dynamin-related protein 1-catalyzed mitochondrial fission through a conserved disordered C-terminal Short Linear Motif",

abstract = "The mechanochemical GTPase dynamin-related protein 1 (Drp1) catalyzes mitochondrial fission, but the regulatory mechanisms remain ambiguous. Here we found that a conserved, intrinsically disordered, six-residue S hort Li near M otif at the extreme Drp1 C-terminus, named CT-SLiM, constitutes a critical allosteric site that controls Drp1 structure and function in vitro and in vivo . Extension of the CT-SLiM by non-native residues, or its interaction with the protein partner GIPC-1, constrains Drp1 subunit conformational dynamics, alters self-assembly properties, and limits cooperative GTP hydrolysis, leading to the fission of model membranes in vitro . In vivo , the availability of the native CT-SLiM is a requirement for productive mitochondrial fission, as both non-native extension and deletion of the CT-SLiM severely impair its progression. Thus, contrary to prevailing models, Drp1-catalyzed mitochondrial fission relies on allosteric communication mediated by the CT-SLiM, deceleration of GTPase activity, and coupled changes in subunit architecture and assembly-disassembly dynamics. ",

author = "Isabel P{\'e}rez-Jover and Kristy Rochon and Di Hu and Mohan, {Pooja Madan} and Isaac Santos-Perez and Gisasola, {Julene Ormaetxea} and Galvez, {Juan Manuel Martinez} and Jon Agirre and Xin Qi and Mears, {Jason A} and Shnyrova, {Anna V} and Rajesh Ramachandran",

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T1 - Allosteric control of dynamin-related protein 1-catalyzed mitochondrial fission through a conserved disordered C-terminal Short Linear Motif

AU - Pérez-Jover, Isabel

AU - Rochon, Kristy

AU - Hu, Di

AU - Mohan, Pooja Madan

AU - Santos-Perez, Isaac

AU - Gisasola, Julene Ormaetxea

AU - Galvez, Juan Manuel Martinez

AU - Agirre, Jon

AU - Qi, Xin

AU - Mears, Jason A

AU - Shnyrova, Anna V

AU - Ramachandran, Rajesh

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N2 - The mechanochemical GTPase dynamin-related protein 1 (Drp1) catalyzes mitochondrial fission, but the regulatory mechanisms remain ambiguous. Here we found that a conserved, intrinsically disordered, six-residue S hort Li near M otif at the extreme Drp1 C-terminus, named CT-SLiM, constitutes a critical allosteric site that controls Drp1 structure and function in vitro and in vivo . Extension of the CT-SLiM by non-native residues, or its interaction with the protein partner GIPC-1, constrains Drp1 subunit conformational dynamics, alters self-assembly properties, and limits cooperative GTP hydrolysis, leading to the fission of model membranes in vitro . In vivo , the availability of the native CT-SLiM is a requirement for productive mitochondrial fission, as both non-native extension and deletion of the CT-SLiM severely impair its progression. Thus, contrary to prevailing models, Drp1-catalyzed mitochondrial fission relies on allosteric communication mediated by the CT-SLiM, deceleration of GTPase activity, and coupled changes in subunit architecture and assembly-disassembly dynamics.

AB - The mechanochemical GTPase dynamin-related protein 1 (Drp1) catalyzes mitochondrial fission, but the regulatory mechanisms remain ambiguous. Here we found that a conserved, intrinsically disordered, six-residue S hort Li near M otif at the extreme Drp1 C-terminus, named CT-SLiM, constitutes a critical allosteric site that controls Drp1 structure and function in vitro and in vivo . Extension of the CT-SLiM by non-native residues, or its interaction with the protein partner GIPC-1, constrains Drp1 subunit conformational dynamics, alters self-assembly properties, and limits cooperative GTP hydrolysis, leading to the fission of model membranes in vitro . In vivo , the availability of the native CT-SLiM is a requirement for productive mitochondrial fission, as both non-native extension and deletion of the CT-SLiM severely impair its progression. Thus, contrary to prevailing models, Drp1-catalyzed mitochondrial fission relies on allosteric communication mediated by the CT-SLiM, deceleration of GTPase activity, and coupled changes in subunit architecture and assembly-disassembly dynamics.

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