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Submitted on October 20, 2003
Accepted on April 12, 2004
Department of Physiology and Biophysics, The University of Iowa Carver College of Medicine, Iowa City, IA 52242
* To whom correspondence should be addressed. E-mail: deborah-segaloff{at}uiowa.edu.
Most loss-of-function mutations of the glycoprotein hormone receptors have been found to be due to the misfolding of the receptor, resulting in its intracellular retention and, therefore, decreased cell surface expression. Chaperone proteins within the endoplasmic reticulum play an essential role in facilitating the folding of newly synthesized proteins and in recognizing and segregating misfolded proteins, thereby preventing their transit to the Golgi. The present study was conducted to begin to elucidate the role of chaperone proteins in the folding of the glycoprotein hormone receptors and misfolded mutants thereof. Toward this end, we examined the potential associations of calnexin, calreticulin, Grp94, BiP, ERp57, and PDI with each of the three glycoprotein hormone receptors. Calnexin, calreticulin, and PDI, were found to associate with the immature forms of all three wild-type glycoprotein hormone receptors. As examples of misfolded glycoprotein hormone receptors, we studied two hLHR loss-of-function mutants that we show to be expressed predominantly as immature forms that are retained intracellularly. Significantly, the patterns of chaperone protein associations with the misfolded hLHR mutants differ from that observed with the wild-type hLHR. Furthermore, and unexpectedly, the chaperone protein associations were found to differ between the two misfolded hLHR mutants. Altogether, our studies show that although the same chaperone proteins are used by the three wild-type (wt) glycoprotein hormone receptors, different chaperone proteins associate with misfolded mutants thereof and the specificity of interactions can vary between mutants, most likely reflecting the different stages of folding they achieve before being targeted for degradation.
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