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Compromised mutant EFEMP1 secretion associated with macular dystrophy remedied by proteostasis network alteration

Academic Article
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Overview

authors

  • Hulleman, J. D.
  • Kaushal, S.
  • Balch, William E.
  • Kelly, Jeffery

publication date

  • December 2011

journal

  • Molecular Biology of the Cell  Journal

abstract

  • An Arg345Trp (R345W) mutation in epidermal growth factor-containing, fibulin-like extracellular matrix protein 1 (EFEMP1) causes its inefficient secretion and the macular dystrophy malattia leventinese/Doyne honeycomb retinal dystrophy (ML/DHRD). To understand the influence of the protein homeostasis (or proteostasis) network in rescuing mutant EFEMP1 misfolding and inefficient secretion linked to ML/DHRD, we developed a convenient and sensitive cell-based luminescence assay to monitor secretion versus intracellular accumulation. Fusing EFEMP1 to Gaussia luciferase faithfully recapitulates mutant EFEMP1 secretion defects observed previously using more cumbersome methodology. To understand what governs mutant intracellular retention, we generated a series of R345 mutants. These mutants revealed that aromatic residue substitutions (i.e., Trp, Tyr, and Phe) at position 345 cause significant EFEMP1 secretion deficiencies. These secretion defects appear to be caused, in part, by reduced native disulfide bonding in domain 6 harboring the 345 position. Finally, we demonstrate that mutant EFEMP1 secretion and proper disulfide formation are enhanced by adaptation of the cellular environment by a reduced growth temperature and/or translational attenuation. This study highlights the mechanisms underlying the inefficient secretion of R345W EFEMP1 and demonstrates that alteration of the proteostasis network may provide a strategy to alleviate or delay the onset of this macular dystrophy.

subject areas

  • Amino Acid Substitution
  • Disulfides
  • Extracellular Matrix Proteins
  • HEK293 Cells
  • Humans
  • Macular Degeneration
  • Mutation, Missense
  • Protein Folding
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Identity

PubMed Central ID

  • PMC3237620

International Standard Serial Number (ISSN)

  • 1059-1524

Digital Object Identifier (DOI)

  • 10.1091/mbc.E11-08-0695

PubMed ID

  • 22031286
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Additional Document Info

start page

  • 4765

end page

  • 4775

volume

  • 22

issue

  • 24

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