The LisH motif of muskelin is crucial for oligomerization and governs intracellular localization

Structure. 2015 Feb 3;23(2):364-73. doi: 10.1016/j.str.2014.11.016. Epub 2015 Jan 8.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 1-Alkyl-2-acetylglycerophosphocholine Esterase / genetics
  • Animals
  • Cell Adhesion Molecules / chemistry*
  • Cell Adhesion Molecules / metabolism*
  • Cell Nucleus / metabolism
  • Crystallography, X-Ray
  • Cytoplasm / metabolism
  • Dimerization
  • Electrophoresis, Polyacrylamide Gel
  • Intracellular Signaling Peptides and Proteins / chemistry*
  • Intracellular Signaling Peptides and Proteins / metabolism*
  • Mice
  • Microtubule-Associated Proteins / genetics
  • Models, Molecular*
  • Neurons / metabolism*
  • Protein Conformation


  • Cell Adhesion Molecules
  • Intracellular Signaling Peptides and Proteins
  • Microtubule-Associated Proteins
  • Mkln1 protein, mouse
  • 1-Alkyl-2-acetylglycerophosphocholine Esterase
  • Pafah1b1 protein, mouse

Associated data

  • PDB/4OYU