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Identification of the low density lipoprotein (ldl) receptor-related protein-1 interactome in central nervous system myelin suggests a role in the clearance of necrotic cell debris

Academic Article
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Overview

authors

  • Fernandez-Castaneda, A.
  • Arandjelovic, S.
  • Stiles, T. L.
  • Schlobach, R. K.
  • Mowen, Kerri
  • Gonias, S. L.
  • Gaultier, A.

publication date

  • February 2013

journal

  • Journal of Biological Chemistry  Journal

abstract

  • In the central nervous system (CNS), fast neuronal signals are facilitated by the oligodendrocyte-produced myelin sheath. Oligodendrocyte turnover or injury generates myelin debris that is usually promptly cleared by phagocytic cells. Failure to remove dying oligodendrocytes leads to accumulation of degraded myelin, which, if recognized by the immune system, may contribute to the development of autoimmunity in diseases such as multiple sclerosis. We recently identified low density lipoprotein receptor-related protein-1 (LRP1) as a novel phagocytic receptor for myelin debris. Here, we report characterization of the LRP1 interactome in CNS myelin. Fusion proteins were designed corresponding to the extracellular ligand-binding domains of LRP1. LRP1 partners were isolated by affinity purification and characterized by mass spectrometry. We report that LRP1 binds intracellular proteins via its extracellular domain and functions as a receptor for necrotic cells. Peptidyl arginine deiminase-2 and cyclic nucleotide phosphodiesterase are novel LRP1 ligands identified in our screen, which interact with full-length LRP1. Furthermore, the extracellular domain of LRP1 is a target of peptidyl arginine deiminase-2-mediated deimination in vitro. We propose that LRP1 functions as a receptor for endocytosis of intracellular components released during cellular damage and necrosis.

subject areas

  • Animals
  • Apoptosis
  • Central Nervous System
  • Citrulline
  • Cloning, Molecular
  • Endocytosis
  • Glutathione Transferase
  • Green Fluorescent Proteins
  • Homeostasis
  • Humans
  • Jurkat Cells
  • Ligands
  • Low Density Lipoprotein Receptor-Related Protein-1
  • Mass Spectrometry
  • Mice
  • Multiple Sclerosis
  • Myelin Sheath
  • Necrosis
  • Phagocytosis
  • Proteomics
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Identity

PubMed Central ID

  • PMC3576060

International Standard Serial Number (ISSN)

  • 0021-9258

Digital Object Identifier (DOI)

  • 10.1074/jbc.M112.384693

PubMed ID

  • 23264627
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Additional Document Info

start page

  • 4538

end page

  • 4548

volume

  • 288

issue

  • 7

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