Endoplasmic reticulum retention of the gamma-secretase complex component Pen2 by Rer1

EMBO Rep. 2007 Aug;8(8):743-8. doi: 10.1038/sj.embor.7401027. Epub 2007 Jul 6.

Abstract

gamma-Secretase is involved in the production of amyloid beta-peptide, which is the principal component of amyloid plaques in the brains of patients with Alzheimer disease. gamma-Secretase is a complex composed of presenilin (PS), nicastrin, anterior pharynx-defective phenotype 1 (Aph1) and PS enhancer 2 (Pen2). We previously proposed a mechanism of complex assembly by which unassembled subunits are retained in the endoplasmic reticulum (ER) and only the fully assembled complex is exported from the ER. We have now identified Retention in endoplasmic reticulum 1 (Rer1) as a protein that is involved in the retention/retrieval of unassembled Pen2 to the ER. Direct binding of unassembled Pen2 to Rer1 is mediated by the first transmembrane domain of Pen2, and a conserved asparagine in this domain is required. Downregulation of Rer1 leads to increased surface localization of Pen2, whereas overexpression of Rer1 stabilizes unassembled Pen2. To our knowledge, Rer1 is the first identified interaction partner of mammalian transmembrane-based retention/retrieval signals.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Vesicular Transport
  • Amino Acid Motifs
  • Amyloid Precursor Protein Secretases / chemistry
  • Amyloid Precursor Protein Secretases / genetics
  • Amyloid Precursor Protein Secretases / metabolism*
  • Asparagine / chemistry
  • Asparagine / genetics
  • Cell Line
  • Endoplasmic Reticulum / chemistry
  • Endoplasmic Reticulum / metabolism*
  • Humans
  • Immunoprecipitation
  • Membrane Glycoproteins / metabolism*
  • Membrane Proteins / chemistry
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism*
  • Protein Structure, Tertiary

Substances

  • Adaptor Proteins, Vesicular Transport
  • Membrane Glycoproteins
  • Membrane Proteins
  • PSENEN protein, human
  • RER1 protein, human
  • Asparagine
  • Amyloid Precursor Protein Secretases