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

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 () and Rajesh Ramachandran ()
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Isabel Pérez-Jover: University of the Basque Country
Kristy Rochon: Case Western Reserve University School of Medicine
Di Hu: Case Western Reserve University School of Medicine
Mukesh Mahajan: Case Western Reserve University School of Medicine
Pooja Madan Mohan: Case Western Reserve University School of Medicine
Isaac Santos-Pérez: Bizkaia Science and Technology
Julene Ormaetxea Gisasola: University of the Basque Country
Juan Manuel Martinez Galvez: University of the Basque Country
Jon Agirre: University of York, Heslington
Xin Qi: Case Western Reserve University School of Medicine
Jason A. Mears: Case Western Reserve University School of Medicine
Anna V. Shnyrova: University of the Basque Country
Rajesh Ramachandran: Case Western Reserve University School of Medicine

Nature Communications, 2024, vol. 15, issue 1, 1-17

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-023-44413-6

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