Allosteric control of dynamin-related protein 1 through a disordered C-terminal Short Linear Motif
Abstract The mechanochemical GTPase dynamin-related protein 1 (Drp1) catalyzes mitochondrial and peroxisomal fission, but the regulatory mechanisms remain ambiguous. Here we find that a conserved, intrinsically disordered, six-residue Short Linear Motif at the extreme Drp1 C-terminus, named CT-SLiM,...
| Main Authors: | , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2024-01-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-023-44413-6 |
| _version_ | 1797363125714944000 |
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| author | Isabel Pérez-Jover Kristy Rochon Di Hu Mukesh Mahajan Pooja Madan Mohan Isaac Santos-Pérez Julene Ormaetxea Gisasola Juan Manuel Martinez Galvez Jon Agirre Xin Qi Jason A. Mears Anna V. Shnyrova Rajesh Ramachandran |
| author_facet | Isabel Pérez-Jover Kristy Rochon Di Hu Mukesh Mahajan Pooja Madan Mohan Isaac Santos-Pérez Julene Ormaetxea Gisasola Juan Manuel Martinez Galvez Jon Agirre Xin Qi Jason A. Mears Anna V. Shnyrova Rajesh Ramachandran |
| author_sort | Isabel Pérez-Jover |
| collection | DOAJ |
| description | Abstract The mechanochemical GTPase dynamin-related protein 1 (Drp1) catalyzes mitochondrial and peroxisomal fission, but the regulatory mechanisms remain ambiguous. Here we find that a conserved, intrinsically disordered, six-residue Short Linear Motif 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, surprisingly leading to the fission of model membranes in vitro. In vivo, the involvement of the native CT-SLiM is critical for productive mitochondrial and peroxisomal fission, as both deletion and non-native extension of the CT-SLiM severely impair their progression. Thus, contrary to prevailing models, Drp1-catalyzed membrane fission relies on allosteric communication mediated by the CT-SLiM, deceleration of GTPase activity, and coupled changes in subunit architecture and assembly-disassembly dynamics. |
| first_indexed | 2024-03-08T16:16:48Z |
| format | Article |
| id | doaj.art-de04eb6b03704799b410f8586ef1b1f7 |
| institution | Directory Open Access Journal |
| issn | 2041-1723 |
| language | English |
| last_indexed | 2024-03-08T16:16:48Z |
| publishDate | 2024-01-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj.art-de04eb6b03704799b410f8586ef1b1f72024-01-07T12:33:57ZengNature PortfolioNature Communications2041-17232024-01-0115111710.1038/s41467-023-44413-6Allosteric control of dynamin-related protein 1 through a disordered C-terminal Short Linear MotifIsabel Pérez-Jover0Kristy Rochon1Di Hu2Mukesh Mahajan3Pooja Madan Mohan4Isaac Santos-Pérez5Julene Ormaetxea Gisasola6Juan Manuel Martinez Galvez7Jon Agirre8Xin Qi9Jason A. Mears10Anna V. Shnyrova11Rajesh Ramachandran12Department of Biochemistry and Molecular Biology, University of the Basque CountryDepartment of Pharmacology, Case Western Reserve University School of MedicineDepartment of Physiology and Biophysics, Case Western Reserve University School of MedicineDepartment of Physiology and Biophysics, Case Western Reserve University School of MedicineDepartment of Physiology and Biophysics, Case Western Reserve University School of MedicineElectron Microscopy and Crystallography Center for Cooperative Research in Biosciences (CIC bioGUNE), Bizkaia Science and TechnologyDepartment of Biochemistry and Molecular Biology, University of the Basque CountryDepartment of Biochemistry and Molecular Biology, University of the Basque CountryYork Structural Biology Laboratory, Department of Chemistry, University of York, HeslingtonDepartment of Physiology and Biophysics, Case Western Reserve University School of MedicineDepartment of Pharmacology, Case Western Reserve University School of MedicineDepartment of Biochemistry and Molecular Biology, University of the Basque CountryDepartment of Physiology and Biophysics, Case Western Reserve University School of MedicineAbstract The mechanochemical GTPase dynamin-related protein 1 (Drp1) catalyzes mitochondrial and peroxisomal fission, but the regulatory mechanisms remain ambiguous. Here we find that a conserved, intrinsically disordered, six-residue Short Linear Motif 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, surprisingly leading to the fission of model membranes in vitro. In vivo, the involvement of the native CT-SLiM is critical for productive mitochondrial and peroxisomal fission, as both deletion and non-native extension of the CT-SLiM severely impair their progression. Thus, contrary to prevailing models, Drp1-catalyzed membrane fission relies on allosteric communication mediated by the CT-SLiM, deceleration of GTPase activity, and coupled changes in subunit architecture and assembly-disassembly dynamics.https://doi.org/10.1038/s41467-023-44413-6 |
| spellingShingle | Isabel Pérez-Jover Kristy Rochon Di Hu Mukesh Mahajan Pooja Madan Mohan Isaac Santos-Pérez Julene Ormaetxea Gisasola Juan Manuel Martinez Galvez Jon Agirre Xin Qi Jason A. Mears Anna V. Shnyrova Rajesh Ramachandran Allosteric control of dynamin-related protein 1 through a disordered C-terminal Short Linear Motif Nature Communications |
| title | Allosteric control of dynamin-related protein 1 through a disordered C-terminal Short Linear Motif |
| title_full | Allosteric control of dynamin-related protein 1 through a disordered C-terminal Short Linear Motif |
| title_fullStr | Allosteric control of dynamin-related protein 1 through a disordered C-terminal Short Linear Motif |
| title_full_unstemmed | Allosteric control of dynamin-related protein 1 through a disordered C-terminal Short Linear Motif |
| title_short | Allosteric control of dynamin-related protein 1 through a disordered C-terminal Short Linear Motif |
| title_sort | allosteric control of dynamin related protein 1 through a disordered c terminal short linear motif |
| url | https://doi.org/10.1038/s41467-023-44413-6 |
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