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The relaxin receptor RXFP1 signals through a mechanism of autoinhibition

Sarah C. Erlandson, Shaun Rawson, James Osei-Owusu, Kelly P. Brock, Xinyue Liu, Joao A. Paulo, Julian Mintseris, Steven P. Gygi, Debora S. Marks, View ORCID ProfileXiaojing Cong, View ORCID ProfileAndrew C. Kruse
doi: https://doi.org/10.1101/2022.01.22.477343
Sarah C. Erlandson
1Department of Biological Chemistry and Molecular Pharmacology, Blavatnik Institute, Harvard Medical School, Boston, Massachusetts 02115, USA
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Shaun Rawson
1Department of Biological Chemistry and Molecular Pharmacology, Blavatnik Institute, Harvard Medical School, Boston, Massachusetts 02115, USA
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James Osei-Owusu
1Department of Biological Chemistry and Molecular Pharmacology, Blavatnik Institute, Harvard Medical School, Boston, Massachusetts 02115, USA
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Kelly P. Brock
2Department of Systems Biology, Blavatnik Institute, Harvard Medical School, Boston, Massachusetts 02115, USA
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Xinyue Liu
1Department of Biological Chemistry and Molecular Pharmacology, Blavatnik Institute, Harvard Medical School, Boston, Massachusetts 02115, USA
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Joao A. Paulo
1Department of Biological Chemistry and Molecular Pharmacology, Blavatnik Institute, Harvard Medical School, Boston, Massachusetts 02115, USA
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Julian Mintseris
1Department of Biological Chemistry and Molecular Pharmacology, Blavatnik Institute, Harvard Medical School, Boston, Massachusetts 02115, USA
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Steven P. Gygi
1Department of Biological Chemistry and Molecular Pharmacology, Blavatnik Institute, Harvard Medical School, Boston, Massachusetts 02115, USA
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Debora S. Marks
2Department of Systems Biology, Blavatnik Institute, Harvard Medical School, Boston, Massachusetts 02115, USA
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Xiaojing Cong
3Institut de Génomique Fonctionnelle, Université de Montpellier, CNRS, INSERM 34094 Montpellier Cedex 5, France
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  • ORCID record for Xiaojing Cong
Andrew C. Kruse
1Department of Biological Chemistry and Molecular Pharmacology, Blavatnik Institute, Harvard Medical School, Boston, Massachusetts 02115, USA
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  • ORCID record for Andrew C. Kruse
  • For correspondence: andrew_kruse@hms.harvard.edu
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Abstract

The relaxin family peptide receptor 1 (RXFP1) is the receptor for relaxin-2, an important regulator of reproductive and cardiovascular physiology. RXFP1 is a multi-domain G protein-coupled receptor (GPCR) with an ectodomain consisting of an LDLa module and leucine-rich repeats. The mechanism of RXFP1 signal transduction is clearly distinct from that of other GPCRs, but remains very poorly understood. Here, we present the cryo-electron microscopy structure of active-state human RXFP1, bound to a single-chain version of the endogenous agonist relaxin-2 and to the heterotrimeric Gs protein. Evolutionary coupling analysis and structure-guided functional experiments reveal that RXFP1 signals through a mechanism of autoinhibition, wherein the receptor’s extracellular loop 2 occupies the orthosteric site in the active state but is inhibited by the ectodomain in the absence of relaxin-2. Our results explain how an unusual GPCR family functions, providing a path to rational drug development targeting the relaxin receptors.

Competing Interest Statement

A.C.K. and S.C.E are inventors on a patent application for engineered single-chain relaxin proteins. A.C.K. is a co-founder and consultant for Tectonic Therapeutic and Seismic Therapeutic and for the Institute for Protein Innovation, a non-profit research institute.

Footnotes

  • Addition of new data regarding the small-molecule agonist ML290, as well as other minor revisions.

Copyright 
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-NC-ND 4.0 International license.
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Posted September 19, 2022.
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The relaxin receptor RXFP1 signals through a mechanism of autoinhibition
Sarah C. Erlandson, Shaun Rawson, James Osei-Owusu, Kelly P. Brock, Xinyue Liu, Joao A. Paulo, Julian Mintseris, Steven P. Gygi, Debora S. Marks, Xiaojing Cong, Andrew C. Kruse
bioRxiv 2022.01.22.477343; doi: https://doi.org/10.1101/2022.01.22.477343
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The relaxin receptor RXFP1 signals through a mechanism of autoinhibition
Sarah C. Erlandson, Shaun Rawson, James Osei-Owusu, Kelly P. Brock, Xinyue Liu, Joao A. Paulo, Julian Mintseris, Steven P. Gygi, Debora S. Marks, Xiaojing Cong, Andrew C. Kruse
bioRxiv 2022.01.22.477343; doi: https://doi.org/10.1101/2022.01.22.477343

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