Glycan in mutations role of CMT 1A and DSS

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Abstract from J Biol Chem. 2004 Nov 10

Glycan-independent role of calnexin in the intracellular retention of

CMT 1A Gas3/PMP22 mutants.

Fontanini A, Chies R, Snapp EL, Ferrarini M, Fabrizi GM, Brancolini C.

Scienze e Tecnologie Biomediche, University of Udine, Udine, Ud 33100.

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 GFP, in a

glycan-independent manner. In addition, photobleaching experiments in

living cells revealed that Gas3/PMP22-GFP 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.