Two di-leucine motifs regulate trafficking of mucolipin-1 to lysosomes

Traffic. 2006 Mar;7(3):337-53. doi: 10.1111/j.1600-0854.2006.00387.x.


Mutations in the mucolipin-1 gene have been linked to mucolipidosis type IV, a lysosomal storage disorder characterized by severe neurological and ophthalmologic abnormalities. Mucolipin-1 is a membrane protein containing six putative transmembrane domains with both its N- and C-termini localized facing the cytosol. To gain information on the sorting motifs that mediate the trafficking of this protein to lysosomes, we have generated chimeras in which the N- and C- terminal tail portions of mucolipin-1 were fused to a reporter gene. In this article, we report the identification of two separate di-leucine-type motifs that co-operate to regulate the transport of mucolipin-1 to lysosomes. One di-leucine motif is positioned at the N-terminal cytosolic tail and mediates direct transport to lysosomes, whereas the other di-leucine motif is found at the C-terminal tail and functions as an adaptor protein 2-dependent internalization motif. We have also found that the C-terminal tail of mucolipin-1 is palmitoylated and that this modification might regulate the efficiency of endocytosis. Finally, the mutagenesis of both di-leucine motifs abrogated lysosomal accumulation and resulted in cell-surface redistribution of mucolipin-1. Taken together, these results reveal novel information regarding the motifs that regulate mucolipin-1 trafficking and suggest a role for palmitoylation in protein sorting.

Publication types

  • Research Support, N.I.H., Intramural

MeSH terms

  • Alanine / metabolism
  • Amino Acid Motifs
  • Amino Acid Sequence
  • Amino Acid Substitution
  • Cysteine / chemistry
  • Cytosol / metabolism
  • Endocytosis
  • Fluorescent Antibody Technique, Indirect
  • Green Fluorescent Proteins / metabolism
  • HeLa Cells
  • Humans
  • Leucine / chemistry*
  • Lysosomes / metabolism*
  • Microscopy, Confocal
  • Models, Chemical
  • Molecular Sequence Data
  • Mutagenesis, Site-Directed
  • Palmitic Acid / metabolism
  • Protein Structure, Tertiary
  • Protein Transport
  • Recombinant Proteins / chemistry
  • Recombinant Proteins / metabolism
  • TRPM Cation Channels / chemistry
  • TRPM Cation Channels / genetics
  • TRPM Cation Channels / metabolism*
  • Transient Receptor Potential Channels


  • MCOLN1 protein, human
  • Recombinant Proteins
  • TRPM Cation Channels
  • Transient Receptor Potential Channels
  • Green Fluorescent Proteins
  • Palmitic Acid
  • Leucine
  • Cysteine
  • Alanine