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

Research output: Working paperPreprint


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 languageEnglish
PublisherResearch Square
Publication statusPublished - 13 Jul 2023

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