Intracellularly located misfolded glycoprotein hormone receptors associate with different chaperone proteins than their cognate wild-type receptors

D Mizrachi; D L Segaloff

doi:10.1210/me.2003-0406

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Intracellularly located misfolded glycoprotein hormone receptors associate with different chaperone proteins than their cognate wild-type receptors

Journal article

Open access

Peer reviewed

Intracellularly located misfolded glycoprotein hormone receptors associate with different chaperone proteins than their cognate wild-type receptors

D Mizrachi and D L Segaloff

Molecular endocrinology (Baltimore, Md.), Vol.18(7), pp.1768-1777

07/2004

DOI: 10.1210/me.2003-0406

PMID: 15105436

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Abstract

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 protein disulfide-isomerase with each of the three glycoprotein hormone receptors. Calnexin, calreticulin, and protein disulfide-isomerase were found to associate with the immature forms of all three wild-type (wt) glycoprotein hormone receptors. As examples of misfolded glycoprotein hormone receptors, we studied two human LH receptor (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 wt 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 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.

Receptors, LH - chemistry

Molecular Chaperones - metabolism

Receptors, FSH - chemistry

Protein Disulfide-Isomerases - metabolism

Receptors, Thyrotropin - metabolism

Heat-Shock Proteins - metabolism

Humans

Cells, Cultured

Molecular Chaperones - genetics

Receptors, LH - metabolism

Molecular Chaperones - chemistry

Protein Folding

HSP70 Heat-Shock Proteins - metabolism

Transfection

Receptors, LH - genetics

Calreticulin - metabolism

Membrane Proteins - metabolism

Calnexin - metabolism

Isomerases - metabolism

Mutation

Receptors, Thyrotropin - chemistry

Receptors, FSH - metabolism

Details

Title: Subtitle: Intracellularly located misfolded glycoprotein hormone receptors associate with different chaperone proteins than their cognate wild-type receptors
Creators: D Mizrachi - Department of Physiology and Biophysics, The University of Iowa Carver College of Medicine, Iowa City, Iowa 52242, USA
D L Segaloff
Resource Type: Journal article
Publication Details: Molecular endocrinology (Baltimore, Md.), Vol.18(7), pp.1768-1777
DOI: 10.1210/me.2003-0406
PMID: 15105436
ISSN: 0888-8809
eISSN: 1944-9917
Grant note: HD22196 / NICHD NIH HHS DK25295 / NIDDK NIH HHS
Language: English
Date published: 07/2004
Academic Unit: Molecular Physiology and Biophysics; Obstetrics and Gynecology
Record Identifier: 9984083997202771

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