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J. Biol. Chem., Vol. 280, Issue 3, 2378-2387, January 21, 2005

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

Alessandra Fontanini, Romina Chies, Erik L. Snapp¶, Moreno Ferrarini||, Gian Maria Fabrizi||, and Claudio Brancolini**

From the Dipartimento di Scienze e Tecnologie Biomediche, Sezione di Biologia and MATI Center of Excellence, Universitá di Udine, Piazza le Kolbe 4, 33100 Udine, Italy, ^¶Cell Biology and Metabolism Branch, NICHD, National Institutes of Health, Bethesda, Maryland 20892, and ^||Department of Neurological and Visual Science, Section of Clinical Neurology, Policlinico GB Rossi, Piazza le LA Scuro 1, 37134 Verona, Italy

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.

Received for publication, May 7, 2004 , and in revised form, November 2, 2004.

^* This work was supported by Ministero dell'Istruzione, dell'Università e della Ricerca Progetto COFIN-2002 (to C. B.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^** To whom correspondence should be addressed. E-mail: cbrancolini{at}makek.dstb.uniud.it.

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