title: Glutathione-conjugating and membrane-remodeling activity of GDAP1 relies on amphipathic C-terminal domain.
abstract: Mutations in the ganglioside-induced differentiation associated protein 1 (GDAP1) cause severe peripheral motor and sensory neuropathies called Charcot-Marie-Tooth disease. GDAP1 expression induces fission of mitochondria and peroxisomes by a currently elusive mechanism, while disease causing mutations in GDAP1 impede the protein's role in mitochondrial dynamics. In silico analysis reveals sequence similarities of GDAP1 to glutathione S-transferases (GSTs). However, a proof of GST activity and its possible impact on membrane dynamics are lacking to date. Using recombinant protein, we demonstrate for the first time theta-class-like GST activity for GDAP1, and it's activity being regulated by the C-terminal hydrophobic domain 1 (HD1) of GDAP1 in an autoinhibitory manner. Moreover, we show that the HD1 amphipathic pattern is required to induce membrane dynamics by GDAP1. As both, fission and GST activities of GDAP1, are critically dependent on HD1, we propose that GDAP1 undergoes a molecular switch, turning from a pro-fission active to an auto-inhibited inactive conformation.
authors.affiliation: Institute of Molecular Health Sciences, Department of Biology, ETH Zürich, Swiss Federal Institute of Technology, 8093 Zurich, Switzerland.|Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, CA, USA.
authors.forename: Nina
authors.initials: N
authors.lastname: Huber
authors.affiliation: European Molecular Biology Laboratory, Grenoble Outstation, 38042 Grenoble, France.|Roche Pharma Research and Early Development, Infectious Diseases Discovery, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, Grenzacherstrasse 124, 4070 Basel, Switzerland.
authors.forename: Christoph
authors.initials: C
authors.lastname: Bieniossek
authors.affiliation: Institute of Molecular Health Sciences, Department of Biology, ETH Zürich, Swiss Federal Institute of Technology, 8093 Zurich, Switzerland.
authors.forename: Konstanze Marion
authors.initials: KM
authors.lastname: Wagner
authors.affiliation: Department of Cytobiology and Cytopathobiology, Philipps University of Marburg, 35033 Marburg, Germany.
authors.forename: Hans-Peter
authors.initials: HP
authors.lastname: Elsässer
authors.affiliation: Institute of Molecular Health Sciences, Department of Biology, ETH Zürich, Swiss Federal Institute of Technology, 8093 Zurich, Switzerland.
authors.forename: Ueli
authors.initials: U
authors.lastname: Suter
authors.affiliation: European Molecular Biology Laboratory, Grenoble Outstation, 38042 Grenoble, France.|School of Biochemistry, Bristol University, Bristol BS8 1TD, United Kingdom.
authors.forename: Imre
authors.initials: I
authors.lastname: Berger
authors.affiliation: Institute of Molecular Health Sciences, Department of Biology, ETH Zürich, Swiss Federal Institute of Technology, 8093 Zurich, Switzerland.
authors.forename: Axel
authors.initials: A
authors.lastname: Niemann
mesh_terms: D000818:Animals; D002462:Cell Membrane / Q000378:metabolism*; D005978:Glutathione / Q000378:metabolism*; D005982:Glutathione Transferase / Q000378:metabolism; D057809:HEK293 Cells; D006706:Homeostasis; D006801:Humans; D008081:Liposomes / Q000378:metabolism; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D000072417:Protein Domains; D055503:Protein Multimerization; D061987:Sf9 Cells
chemical_list: C118663:GDAP protein; D008081:Liposomes; D009419:Nerve Tissue Proteins; D005982:Glutathione Transferase; D005978:Glutathione