Direct observation of individual endogenous protein complexes in situ by proximity ligation
Abstract
Cellular processes can only be understood as the dynamic interplay of molecules. There is a need for techniques to monitor interactions of endogenous proteins directly in individual cells and tissues to reveal the cellular and molecular architecture and its responses to perturbations. Here we report our adaptation of the recently developed proximity ligation method to examine the subcellular localization of protein-protein interactions at single-molecule resolution. Proximity probes-oligonucleotides attached to antibodies against the two target proteins-guided the formation of circular DNA strands when bound in close proximity. The DNA circles in turn served as templates for localized rolling-circle amplification (RCA), allowing individual interacting pairs of protein molecules to be visualized and counted in human cell lines and clinical specimens. We used this method to show specific regulation of protein-protein interactions between endogenous Myc and Max oncogenic transcription factors in response to interferon-gamma (IFN-gamma) signaling and low-molecular-weight inhibitors.
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In situ PLA has a resolution of 25-30 nm, so the authors cannot exclude that they may detect D2R-OXTR heteroreceptor complexes and/or co-location within the same cell membrane nanodomains.
“As in situ PLA typically provides a resolution in the range of 25–30 nm when secondary IgG antibodies are used (Soderberg et al., 2006; Soderberg et al., 2007), we cannot exclude the possibility that in our current experiments, we may detect D2R–OXTR heteroreceptor complexes and/or the co-location of D2R and OXTR within the same cell membrane nanodomains (hereafter referred to as heterocomplexes).”
From Evidence for the existence of facilitatory interactions between the dopamine D2 receptor and the oxytocin receptor in the amygdala of the rat relevance for anxiolytic actions (2023) · cites this paper as Soderberg et al., 2006
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- Authors
- Söderberg, O., Gullberg, M., Jarvius, M., Ridderstråle, K., Leuchowius, K.-J., Jarvius, J., Wester, K., Hydbring, P., Bahram, F., Larsson, L.-G., & Landegren, U.
- Affiliations
- Uppsala University (SE)
- Swedish University of Agricultural Sciences (SE)
- Corresponding author
- Landegren, Ulf
- ORCID
- Venue
- Nature Methods
- Published
- 2006-10-29
- Volume
- 3
- Issue
- 12
- Pages
- 995-1000
- ISSN
- 1548-7091 (ISSN-L)
- 1548-7105
- OpenAlex
- W1992496728
- Cited by
- 2,419
- References
- 24
- Citations by year
- 2026: 88 · 2025: 90 · 2024: 109 · 2023: 111 · 2022: 149 · 2021: 143 · 2020: 149 · 2019: 171 · 2018: 174 · 2017: 161 · 2016: 202 · 2015: 190 · 2014: 191 · 2013: 152 · 2012: 111
- FWCI
- 9.23
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Methods (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute of Allergy and Infectious Diseases (R01AI121012)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Advanced biosensing and bioanalysis techniques
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biophysics › Advanced Fluorescence Microscopy Techniques
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Biotin and Related Studies
- Keywords
- proximity ligation, protein-protein interaction, single-molecule imaging, subcellular localization, rolling circle amplification, c-Myc, Max, interferon-gamma signaling, low molecular weight inhibitors, transcription factor regulation, clinical samples
- MeSH terms
- Cell Physiological Phenomena, Image Enhancement, Microscopy, Fluorescence, Proteins, Protein Interaction Mapping
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