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PreprintCited by 8Receptor Mechanisms and SignalingCellular transport and secretionLipid Membrane Structure and Behavior

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Membrane curvature association of amphipathic helix 8 drives constitutive endocytosis of GPCRs

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Schmidt, Jan Hendrik, Herlo, Rasmus, Rombach, Joscha, Larsen, Andreas Haahr, Stoklund, Mikkel, Perslev, Mathias, Nielsen, Tommas Theiss Ehlers, Andersen, Keenie Ayla, Herenbrink, Carmen Klein, Lycas, Matthew D., Ejdrup, Aske Lykke, Christensen, Nikolaj Riis, Christensen, Jan P., Salman, Mootaz, Herborg, Freja, Gether, Ulrik, Hauser, Alexander Sebastian, Bassereau, Patricia, Perrais, David, Madsen, Kenneth Lindegaard·2024·Science Advances
DOI 10.1101/2024.03.27.587027PMC PMC12346279

Preprint — published as 10.1126/sciadv.adv1499

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Abstract

Cellular signaling relies on the activity of transmembrane receptors and their presentation on the cellular surface. Their continuous insertion in the plasma membrane is balanced by constitutive and activity dependent internalization, which is orchestrated by adaptor proteins recognizing semi-specific motifs within the receptors’ intracellular regions. Here we describe a complementary and evolutionary conserved and refined trafficking mechanism for G-protein coupled receptors (GPCR). This mechanism relies on the insertion of their amphipathic helix 8 into the inner leaflet of lipid membranes, orthogonal to the transmembrane helices. These amphipathic helices dictate subcellular localization of the receptors and autonomously drive their endocytosis by cooperative assembly and association with areas of high membrane curvature. The strength of helix 8 membrane insertion propensity quantitatively predicts the rate of constitutive internalization of GPCRs. This discovery advances our understanding of membrane protein trafficking and highlights a new principle of receptor-lipid interactions that may have broader implications for cellular signaling and therapeutic targeting. One-Sentence Summary: Receptor proteins navigate cellular membranes by interacting with their curvature using an evolutionary conserved mechanism that relies on amphipathic helices and complements direct coupling to the endocytic protein machinery.

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Metadata

Authors
Schmidt, J. H., Herlo, R., Rombach, J., Larsen, A. H., Stoklund, M., Perslev, M., Nielsen, T. T. E., Andersen, K. A., Herenbrink, C. K., Lycas, M. D., Ejdrup, A. L., Christensen, N. R., Christensen, J. P., Salman, M., Herborg, F., Gether, U., Hauser, A. S., Bassereau, P., Perrais, D., & Madsen, K. L.
Affiliations
  • University of Copenhagen (DK)
  • University of Oxford (GB)
  • Centre National de la Recherche Scientifique (FR)
Corresponding author
Madsen, Kenneth Lindegaard
ORCID
Venue
Science Advances
Publisher
openRxiv
Published
2024-03-28
Volume
11
Issue
33
Pages
eadv1499-eadv1499
ISSN
2375-2548 (ISSN-L)
DOI
10.1101/2024.03.27.587027
PMC
PMC12346279
OpenAlex
W4413115425
Cited by
8
References
2
Citations by year
2026: 7 · 2025: 1
FWCI
2.40
Type
journal article
Language
en
Open access
Licence
Locations
  • Science Advances (publishedVersion, cc-by-nc)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, other-oa)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by-nc)
  • PubMed Central (publishedVersion, cc-by-nc)
  • PubMed (publishedVersion)
  • Research at the University of Copenhagen (University of Copenhagen) (publishedVersion, cc-by-nc)
  • HAL (submittedVersion, other-oa)
Funders
  • Agence Nationale de la Recherche (ANR-10-IDEX-0001)
  • Lundbeckfonden
  • H. Lundbeck A/S
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Lipid Membrane Structure and Behavior
Keywords
G protein-coupled receptors, constitutive endocytosis, membrane curvature, receptor internalization, receptor-lipid interactions, membrane protein trafficking, receptor subcellular localization
MeSH terms
Animals, Cell Membrane, Endocytosis, Humans, Signal Transduction, Protein Transport, Receptors, G-Protein-Coupled, HEK293 Cells

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