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

Author

Listed:
  • João P. L. Coelho

    (Technical University of Munich)

  • Matthias Stahl

    (Technical University of Munich
    Karolinska Institutet)

  • Nicolas Bloemeke

    (Technical University of Munich)

  • Kevin Meighen-Berger

    (Technical University of Munich)

  • Carlos Piedrafita Alvira

    (Technical University of Munich)

  • Zai-Rong Zhang

    (Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences)

  • Stephan A. Sieber

    (Technical University of Munich)

  • Matthias J. Feige

    (Technical University of Munich
    Technical University of Munich)

Abstract

A fundamental step in membrane protein biogenesis is their integration into the lipid bilayer with a defined orientation of each transmembrane segment. Despite this, it remains unclear how cells detect and handle failures in this process. Here we show that single point mutations in the membrane protein connexin 32 (Cx32), which cause Charcot-Marie-Tooth disease, can cause failures in membrane integration. This leads to Cx32 transport defects and rapid degradation. Our data show that multiple chaperones detect and remedy this aberrant behavior: the ER–membrane complex (EMC) aids in membrane integration of low-hydrophobicity transmembrane segments. If they fail to integrate, these are recognized by the ER–lumenal chaperone BiP. Ultimately, the E3 ligase gp78 ubiquitinates Cx32 proteins, targeting them for degradation. Thus, cells use a coordinated system of chaperones for the complex task of membrane protein biogenesis, which can be compromised by single point mutations, causing human disease.

Suggested Citation

  • João P. L. Coelho & Matthias Stahl & Nicolas Bloemeke & Kevin Meighen-Berger & Carlos Piedrafita Alvira & Zai-Rong Zhang & Stephan A. Sieber & Matthias J. Feige, 2019. "A network of chaperones prevents and detects failures in membrane protein lipid bilayer integration," Nature Communications, Nature, vol. 10(1), pages 1-10, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-08632-0
    DOI: 10.1038/s41467-019-08632-0
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