Itch receptor MRGPRX4 interacts with the receptor activity–modifying proteins
Open accessPublished version of a preprint
Abstract
Cholestatic itch is a severe and debilitating symptom in liver diseases with limited treatment options. The class A G protein-coupled receptor (GPCR) Mas-related GPCR subtype X4 (MRGPRX4) has been identified as a receptor for bile acids, which are potential cholestatic pruritogens. An increasing number of GPCRs have been shown to interact with receptor activity-modifying proteins (RAMPs), which can modulate different aspects of GPCR biology. Using a combination of multiplexed immunoassay and proximity ligation assay, we show that MRGPRX4 interacts with RAMPs. The interaction of MRGPRX4 with RAMP2, but not RAMP1 or 3, causes attenuation of basal and agonist-dependent signaling, which correlates with a decrease of MRGPRX4 cell surface expression as measured using a quantitative NanoBRET pulse-chase assay. Finally, we use AlphaFold Multimer to predict the structure of the MRGPRX4-RAMP2 complex. The discovery that RAMP2 regulates MRGPRX4 may have direct implications for future drug development for cholestatic itch.
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Cites
Highly accurate protein structure prediction with AlphaFold
Jumper, J., Evans, R., Pritzel, A., Green, T., Figurnov, M., Ronneberger, O., Tunyasuvunakool, K., Bates, R., Žídek, A., Potapenko, A., et al. (2021) · Nature · doi:10.1038/s41586-021-03819-2 · Cited by 43,764 · see citing works
Protein complex prediction with AlphaFold-Multimer
Evans, R., O’Neill, M., Pritzel, A., Antropova, N., Senior, A., Green, T., Žídek, A., Bates, R., Blackwell, S., Yim, J., et al. (2021) · doi:10.1101/2021.10.04.463034 · Cited by 3,808 · see citing works
In silico design of novel probes for the atypical opioid receptor MRGPRX2
Lansu, K., Karpiak, J., Liu, J., Huang, X.-P., McCorvy, J. D., Kroeze, W. K., Che, T., Nagase, H., Carroll, F. I., Jin, J., et al. (2017) · Nature Chemical Biology · doi:10.1038/nchembio.2334 · Cited by 293 · see citing works
Ins and outs of AlphaFold2 transmembrane protein structure predictions
Hegedűs, T., Geisler, M., Lukács, G. L., & Farkas, B. (2022) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-021-04112-1 · Cited by 127 · see citing works
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- Authors
- Kotliar, I. B., Ceraudo, E., Kemelmakher-Liben, K., Oren, D. A., Lorenzen, E., Dodig-Crnković, T., Horioka-Duplix, M., Huber, T., Schwenk, J. M., & Sakmar, T. P.
- Affiliations
- Tri-Institutional PhD Program in Chemical Biology (US)
- Rockefeller University (US)
- Science for Life Laboratory (SE)
- Karolinska Institutet (SE)
- Corresponding author
- Sakmar, Thomas P.
- ORCID
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2023-05
- Volume
- 299
- Issue
- 5
- Pages
- 104664
- ISSN
- 0021-9258 (ISSN-L)
- PMC
- PMC10165273
- OpenAlex
- W4361264976
- Cited by
- 21
- References
- 4
- Citations by year
- 2026: 11 · 2025: 2 · 2024: 7 · 2023: 1
- FWCI
- 1.87
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- Familjen Erling-Perssons Stiftelse
- Rockefeller University (SCR_017732)
- Robertson Foundation
- Health Promotion Agency
- Knut och Alice Wallenbergs Stiftelse
- National Institutes of Health (GM136640)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
- Life Sciences › Neuroscience › Sensory Systems › Ion Channels and Receptors
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuropeptides and Animal Physiology
- Keywords
- receptor activity-modifying proteins, RAMP2, pruritus, bile acids, G protein-coupled receptor signaling, receptor complex structure, cell surface expression, liver disease
- MeSH terms
- Cell Membrane, Humans, Protein Binding, Pruritus, Signal Transduction, Receptors, G-Protein-Coupled, Receptor Activity-Modifying Proteins, Receptor Activity-Modifying Protein 1, Receptor Activity-Modifying Protein 2, Receptor Activity-Modifying Protein 3
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