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A network of chaperones prevents and detects failures in membrane protein lipid bilayer integration

João P L Coelho1, Matthias Stahl1,2, Nicolas Bloemeke1

  • 1Center for Integrated Protein Science at the Department of Chemistry, Technical University of Munich, Lichtenbergstr. 4, 85748, Garching, Germany.

Nature Communications
|February 10, 2019
PubMed

Insights

Single point mutations in connexin 32 (Cx32) disrupt membrane protein integration, causing disease. Cellular chaperones, including the ER-membrane complex (EMC) and BiP, detect and degrade misintegrated Cx32 to maintain cell health.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Biochemistry

Background:

  • Membrane protein biogenesis requires precise insertion into the lipid bilayer.
  • Failures in membrane protein integration can lead to cellular dysfunction and disease.
  • Connexin 32 (Cx32) mutations are linked to Charcot-Marie-Tooth disease, but the underlying molecular mechanisms are not fully understood.

Purpose of the Study:

  • To investigate how cells detect and manage misintegrated membrane proteins, specifically focusing on connexin 32.
  • To elucidate the role of cellular chaperones in correcting or degrading misfolded membrane proteins.
  • To understand how single point mutations in Cx32 lead to disease phenotypes.

Main Methods:

  • Site-directed mutagenesis of connexin 32 (Cx32).
  • Cellular transport and degradation assays.
  • Immunological detection of Cx32 and chaperone interactions.
  • Analysis of endoplasmic reticulum-associated degradation (ERAD) pathways.

Main Results:

  • Single point mutations in Cx32 can impair its integration into the endoplasmic reticulum membrane.
  • The ER-membrane complex (EMC) assists in integrating transmembrane segments with low hydrophobicity.
  • BiP recognizes and BiP targets misintegrated Cx32 for degradation via the E3 ligase gp78 and subsequent ubiquitination.

Conclusions:

  • Cellular surveillance mechanisms involving multiple chaperones (EMC, BiP) and degradation machinery (gp78) ensure proper membrane protein biogenesis.
  • Defects in Cx32 membrane integration due to mutations disrupt protein transport and lead to degradation, contributing to Charcot-Marie-Tooth disease.
  • This study reveals a coordinated cellular response to misfolded membrane proteins, highlighting the importance of chaperone networks in preventing disease.

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