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The targeting of cystinosin to the lysosomal membrane requires a tyrosine-based signal and a novel sorting motif

Academic Article
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Overview

authors

  • Cherqui, Stephanie
  • Kalatzis, V.
  • Trugnan, G.
  • Antignac, C.

publication date

  • April 2001

journal

  • Journal of Biological Chemistry  Journal

abstract

  • Cystinosis is a lysosomal transport disorder characterized by an accumulation of intra-lysosomal cystine. Biochemical studies showed that the lysosomal cystine transporter was distinct from the plasma membrane cystine transporters and that it exclusively transported cystine. The gene underlying cystinosis, CTNS, encodes a predicted seven-transmembrane domain protein called cystinosin, which is highly glycosylated at the N-terminal end and carries a GY-XX-Phi (where Phi is a hydrophobic residue) lysosomal-targeting motif in its carboxyl tail. We constructed cystinosin-green fluorescent protein fusion proteins to determine the subcellular localization of cystinosin in transfected cell lines and showed that cystinosin-green fluorescent protein colocalizes with lysosomal-associated membrane protein 2 (LAMP-2) to lysosomes. Deletion of the GY-XX-Phi motif resulted in a partial redirection to the plasma membrane as well as sorting to lysosomes, demonstrating that this motif is only partially responsible for the lysosomal targeting of cystinosin and suggesting the existence of a second sorting signal. A complete relocalization of cystinosin to the plasma membrane was obtained after deletion of half of the third cytoplasmic loop (amino acids 280-288) coupled with the deletion of the GY-DQ-L motif, demonstrating the presence of the second signal within this loop. Using site-directed mutagenesis studies we identified a novel conformational lysosomal-sorting motif, the core of which was delineated to YFPQA (amino acids 281-285).

subject areas

  • Amino Acid Sequence
  • Amino Acid Transport Systems, Neutral
  • Animals
  • Binding Sites
  • Cell Line
  • Cystinosis
  • Dogs
  • Glycoproteins
  • Glycosylation
  • HeLa Cells
  • Humans
  • Intracellular Membranes
  • Lysosomes
  • Membrane Proteins
  • Membrane Transport Proteins
  • Models, Molecular
  • Molecular Sequence Data
  • Mutagenesis
  • Mutagenesis, Site-Directed
  • Protein Structure, Secondary
  • Protein Transport
  • Recombinant Proteins
  • Sequence Deletion
  • Signal Transduction
  • Transfection
  • Tyrosine
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Identity

International Standard Serial Number (ISSN)

  • 0021-9258

Digital Object Identifier (DOI)

  • 10.1074/jbc.M010562200

PubMed ID

  • 11150305
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Additional Document Info

start page

  • 13314

end page

  • 13321

volume

  • 276

issue

  • 16

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