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

ABSTRACT: A fundamental step in membrane protein biogenesis is their integration into the lipid bilayer with a defined topology. Despite this, it remains unclear how cells detect and handle failures in membrane integration. Our data 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 its rapid degradation. We found multiple chaperones to 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.

INSTRUMENT(S): Orbitrap Fusion

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Epithelial Cell, Cell Culture

SUBMITTER: Matthias Stahl

LAB HEAD: Stephan A. Sieber

PROVIDER: PXD009189 | Pride | 2019-01-29

REPOSITORIES: Pride

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

Coelho João P L JPL Stahl Matthias M Bloemeke Nicolas N Meighen-Berger Kevin K Alvira Carlos Piedrafita CP Zhang Zai-Rong ZR Sieber Stephan A SA Feige Matthias J MJ

Nature communications 20190208 1

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 cha ...[more]

PMID: 30737405

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