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Molecular basis for the evolved instability of a human G-protein coupled receptor

Membrane proteins are prone to misfolding and degradation. This is particularly true for mammalian forms of the gonadotropin-releasing hormone receptor (GnRHR). Although they function at the plasma membrane, mammalian GnRHRs accumulate within the secretory pathway. Their apparent instability is beli...

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Autores principales: Chamness, Laura M., Zelt, Nathan B., Harrington, Haley R., Kuntz, Charles P., Bender, Brian J., Penn, Wesley D., Ziarek, Joshua J., Meiler, Jens, Schlebach, Jonathan P.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8865034/
https://www.ncbi.nlm.nih.gov/pubmed/34818554
http://dx.doi.org/10.1016/j.celrep.2021.110046
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author Chamness, Laura M.
Zelt, Nathan B.
Harrington, Haley R.
Kuntz, Charles P.
Bender, Brian J.
Penn, Wesley D.
Ziarek, Joshua J.
Meiler, Jens
Schlebach, Jonathan P.
author_facet Chamness, Laura M.
Zelt, Nathan B.
Harrington, Haley R.
Kuntz, Charles P.
Bender, Brian J.
Penn, Wesley D.
Ziarek, Joshua J.
Meiler, Jens
Schlebach, Jonathan P.
author_sort Chamness, Laura M.
collection PubMed
description Membrane proteins are prone to misfolding and degradation. This is particularly true for mammalian forms of the gonadotropin-releasing hormone receptor (GnRHR). Although they function at the plasma membrane, mammalian GnRHRs accumulate within the secretory pathway. Their apparent instability is believed to have evolved through selection for attenuated GnRHR activity. Nevertheless, the molecular basis of this adaptation remains unclear. We show that adaptation coincides with a C-terminal truncation that compromises the translocon-mediated membrane integration of its seventh transmembrane domain (TM7). We also identify a series of polar residues in mammalian GnRHRs that compromise the membrane integration of TM2 and TM6. Reverting a lipid-exposed polar residue in TM6 to an ancestral hydrophobic residue restores expression with no impact on function. Evolutionary trends suggest variations in the polarity of this residue track with reproductive phenotypes. Our findings suggest that the marginal energetics of cotranslational folding can be exploited to tune membrane protein fitness.
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spelling pubmed-88650342022-02-23 Molecular basis for the evolved instability of a human G-protein coupled receptor Chamness, Laura M. Zelt, Nathan B. Harrington, Haley R. Kuntz, Charles P. Bender, Brian J. Penn, Wesley D. Ziarek, Joshua J. Meiler, Jens Schlebach, Jonathan P. Cell Rep Article Membrane proteins are prone to misfolding and degradation. This is particularly true for mammalian forms of the gonadotropin-releasing hormone receptor (GnRHR). Although they function at the plasma membrane, mammalian GnRHRs accumulate within the secretory pathway. Their apparent instability is believed to have evolved through selection for attenuated GnRHR activity. Nevertheless, the molecular basis of this adaptation remains unclear. We show that adaptation coincides with a C-terminal truncation that compromises the translocon-mediated membrane integration of its seventh transmembrane domain (TM7). We also identify a series of polar residues in mammalian GnRHRs that compromise the membrane integration of TM2 and TM6. Reverting a lipid-exposed polar residue in TM6 to an ancestral hydrophobic residue restores expression with no impact on function. Evolutionary trends suggest variations in the polarity of this residue track with reproductive phenotypes. Our findings suggest that the marginal energetics of cotranslational folding can be exploited to tune membrane protein fitness. 2021-11-23 /pmc/articles/PMC8865034/ /pubmed/34818554 http://dx.doi.org/10.1016/j.celrep.2021.110046 Text en https://creativecommons.org/licenses/by/4.0/This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) ).
spellingShingle Article
Chamness, Laura M.
Zelt, Nathan B.
Harrington, Haley R.
Kuntz, Charles P.
Bender, Brian J.
Penn, Wesley D.
Ziarek, Joshua J.
Meiler, Jens
Schlebach, Jonathan P.
Molecular basis for the evolved instability of a human G-protein coupled receptor
title Molecular basis for the evolved instability of a human G-protein coupled receptor
title_full Molecular basis for the evolved instability of a human G-protein coupled receptor
title_fullStr Molecular basis for the evolved instability of a human G-protein coupled receptor
title_full_unstemmed Molecular basis for the evolved instability of a human G-protein coupled receptor
title_short Molecular basis for the evolved instability of a human G-protein coupled receptor
title_sort molecular basis for the evolved instability of a human g-protein coupled receptor
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8865034/
https://www.ncbi.nlm.nih.gov/pubmed/34818554
http://dx.doi.org/10.1016/j.celrep.2021.110046
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