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Molecular Basis for the Evolved Instability of a Human G-Protein Coupled Receptor

Laura M. Chamness, Nathan B. Zelt, Charles P. Kuntz, Brian J. Bender, Wesley D. Penn, Joshua J. Ziarek, Jens Meiler, View ORCID ProfileJonathan P. Schlebach
doi: https://doi.org/10.1101/2019.12.20.884718
Laura M. Chamness
1Department of Chemistry, Indiana University, Bloomington, Indiana, USA
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Nathan B. Zelt
1Department of Chemistry, Indiana University, Bloomington, Indiana, USA
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Charles P. Kuntz
1Department of Chemistry, Indiana University, Bloomington, Indiana, USA
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Brian J. Bender
3Department of Chemistry, Vanderbilt University, Nashville, TN, USA
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Wesley D. Penn
1Department of Chemistry, Indiana University, Bloomington, Indiana, USA
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Joshua J. Ziarek
2Department of Molecular and Cellular Biochemistry, Indiana University, Bloomington, Indiana, USA
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Jens Meiler
3Department of Chemistry, Vanderbilt University, Nashville, TN, USA
4Institut for Drug Development, Leipzig University, Leipzig, SAC, Germany
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Jonathan P. Schlebach
1Department of Chemistry, Indiana University, Bloomington, Indiana, USA
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  • ORCID record for Jonathan P. Schlebach
  • For correspondence: jschleba@indiana.edu
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ABSTRACT

Eukaryotic membrane proteins are prone to misfolding and degradation within the endoplasmic reticulum (ER). This is particularly true for the mammalian forms of the gonadotropin-releasing hormone receptor (GnRHR). Though they function at the plasma membrane, mammalian GnRHRs tend to accumulate within the secretory pathway. Their apparent instability is believed to have evolved in response to a selection for GnRHRs with attenuated activity. Nevertheless, the structural basis of this adaptation remains unclear. An experimental characterization of natural GnRHRs reveals this adaptation coincides with a C-terminal truncation and an increase in the polarity of its transmembrane (TM) domains. We show that this enhanced polarity compromises the translocon-mediated cotranslational folding of two nascent TM domains. Moreover, replacing a conserved polar residue in TM6 with an ancestral hydrophobic residue partially restores GnRHR expression with minimal impact on function. Our findings suggest the marginal energetics of cotranslational folding can be exploited to tune membrane protein fitness.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license.
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Posted December 23, 2019.
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Molecular Basis for the Evolved Instability of a Human G-Protein Coupled Receptor
Laura M. Chamness, Nathan B. Zelt, Charles P. Kuntz, Brian J. Bender, Wesley D. Penn, Joshua J. Ziarek, Jens Meiler, Jonathan P. Schlebach
bioRxiv 2019.12.20.884718; doi: https://doi.org/10.1101/2019.12.20.884718
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Molecular Basis for the Evolved Instability of a Human G-Protein Coupled Receptor
Laura M. Chamness, Nathan B. Zelt, Charles P. Kuntz, Brian J. Bender, Wesley D. Penn, Joshua J. Ziarek, Jens Meiler, Jonathan P. Schlebach
bioRxiv 2019.12.20.884718; doi: https://doi.org/10.1101/2019.12.20.884718

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