title: The LisH motif of muskelin is crucial for oligomerization and governs intracellular localization.
abstract: Neurons regulate the number of surface receptors by balancing the transport to and from the plasma membrane to adjust their signaling properties. The protein muskelin was recently identified as a key factor guiding the transport of α1 subunit-containing GABAA receptors. Here we present the crystal structure of muskelin, comprising its N-terminal discoidin domain and Lis1-homology (LisH) motif. The molecule crystallized as a dimer with the LisH motif exclusively mediating oligomerization. Our subsequent biochemical analyses confirmed that the LisH motif acts as a dimerization element in muskelin. Together with an intermolecular head-to-tail interaction, the LisH-dependent dimerization is required to assemble a muskelin tetramer. Intriguingly, our cellular studies revealed that the loss of this dimerization results in a complete redistribution of muskelin from the cytoplasm to the nucleus and impairs muskelin's function in GABAA receptor transport. These studies demonstrate that the LisH-dependent dimerization is a crucial factor for muskelin function.
authors.affiliation: Rudolf Virchow Center for Experimental Biomedicine, University of Würzburg, D-97080 Würzburg, Germany.
authors.forename: Carolyn F
authors.initials: CF
authors.lastname: Delto
authors.affiliation: Center for Molecular Neurobiology, ZMNH, University Medical Center Hamburg-Eppendorf, D-20251 Hamburg, Germany.
authors.forename: Frank F
authors.initials: FF
authors.lastname: Heisler
authors.affiliation: Rudolf Virchow Center for Experimental Biomedicine, University of Würzburg, D-97080 Würzburg, Germany.
authors.forename: Jochen
authors.initials: J
authors.lastname: Kuper
authors.affiliation: Rudolf Virchow Center for Experimental Biomedicine, University of Würzburg, D-97080 Würzburg, Germany.
authors.forename: Bodo
authors.initials: B
authors.lastname: Sander
authors.affiliation: Center for Molecular Neurobiology, ZMNH, University Medical Center Hamburg-Eppendorf, D-20251 Hamburg, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Kneussel
authors.affiliation: Rudolf Virchow Center for Experimental Biomedicine, University of Würzburg, D-97080 Würzburg, Germany. Electronic address: hermann.schindelin@virchow.uni-wuerzburg.de.
authors.forename: Hermann
authors.initials: H
authors.lastname: Schindelin
mesh_terms: D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase / Q000235:genetics; D000818:Animals; D015815:Cell Adhesion Molecules / Q000737:chemistry* / Q000378:metabolism*; D002467:Cell Nucleus / Q000378:metabolism; D018360:Crystallography, X-Ray; D003593:Cytoplasm / Q000378:metabolism; D019281:Dimerization; D004591:Electrophoresis, Polyacrylamide Gel; D047908:Intracellular Signaling Peptides and Proteins / Q000737:chemistry* / Q000378:metabolism*; D051379:Mice; D008869:Microtubule-Associated Proteins / Q000235:genetics; D008958:Models, Molecular; D009474:Neurons / Q000378:metabolism*; D011487:Protein Conformation
chemical_list: D015815:Cell Adhesion Molecules; D047908:Intracellular Signaling Peptides and Proteins; D008869:Microtubule-Associated Proteins; C503020:Mkln1 protein, mouse; D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase; C513190:Pafah1b1 protein, mouse