Glycan-independent Role of Calnexin in the Intracellular Retention of Charcot-Marie-Tooth 1A Gas3/PMP22 Mutants

Missense point mutations in Gas3/PMP22 are responsible for the peripheral neuropathies Charcot-Marie-Tooth 1A and Dejerine Sottas syndrome. These mutations induce protein misfolding with the consequent accumulation of the proteins in the endoplasmic reticulum and the formation of aggresomes. During...

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Bibliographic Details
Published in:The Journal of biological chemistry 2005-01, Vol.280 (3), p.2378-2387
Main Authors: Fontanini, Alessandra, Chies, Romina, Snapp, Erik L., Ferrarini, Moreno, Fabrizi, Gian Maria, Brancolini, Claudio
Format: Article
Language:English
Subjects:
Base Sequence
Blotting, Western
Calnexin - physiology
Cell Line, Tumor
Charcot-Marie-Tooth Disease - genetics
Charcot-Marie-Tooth Disease - metabolism
DNA Primers
Glycosylation
Humans
Myelin Proteins - genetics
Myelin Proteins - metabolism
Polysaccharides - metabolism
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Summary:Missense point mutations in Gas3/PMP22 are responsible for the peripheral neuropathies Charcot-Marie-Tooth 1A and Dejerine Sottas syndrome. These mutations induce protein misfolding with the consequent accumulation of the proteins in the endoplasmic reticulum and the formation of aggresomes. During folding, Gas3/PMP22 associates with the lectin chaperone calnexin. Here, we show that calnexin interacts with the misfolded transmembrane domains of Gas3/PMP22, fused to green fluorescent protein, in a glycan-independent manner. In addition, photobleaching experiments in living cells revealed that Gas3/PMP22-green fluorescent protein mutants are mobile but diffuse at almost half the diffusion coefficient of wild type protein. Our results support emerging models for a glycan-independent chaperone role for calnexin and for the mechanism of retention of misfolded membrane proteins in the endoplasmic reticulum.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.M405104200