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Single molecule analysis of functionally asymmetric G protein-coupled receptor (GPCR) oligomers reveals diverse spatial and structural assemblies.

Jonas, KC; Fanelli, F; Huhtaniemi, IT; Hanyaloglu, AC (2015) Single molecule analysis of functionally asymmetric G protein-coupled receptor (GPCR) oligomers reveals diverse spatial and structural assemblies. J Biol Chem, 290 (7). pp. 3875-3892. ISSN 1083-351X
SGUL Authors: Jonas, Kim Carol

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Formation of G protein-coupled receptors (GPCRs) into dimers and higher order oligomers represents a key mechanism in pleiotropic signaling, yet how individual protomers function within oligomers remains poorly understood. We present a super-resolution imaging approach, resolving single GPCR molecules to ∼ 8 nm resolution in functional asymmetric dimers and oligomers using dual-color photoactivatable dyes and localization microscopy (PD-PALM). PD-PALM of two functionally defined mutant luteinizing hormone receptors (LHRs), a ligand-binding deficient receptor (LHR(B-)) and a signaling-deficient (LHR(S-)) receptor, which only function via intermolecular cooperation, favored oligomeric over dimeric formation. PD-PALM imaging of trimers and tetramers revealed specific spatial organizations of individual protomers in complexes where the ratiometric composition of LHR(B-) to LHR(S-) modulated ligand-induced signal sensitivity. Structural modeling of asymmetric LHR oligomers strongly aligned with PD-PALM-imaged spatial arrangements, identifying multiple possible helix interfaces mediating inter-protomer associations. Our findings reveal that diverse spatial and structural assemblies mediating GPCR oligomerization may acutely fine-tune the cellular signaling profile.

Item Type: Article
Additional Information: © 2015 by The American Society for Biochemistry and Molecular Biology, Inc. Author's Choice—Final version full access. Creative Commons Attribution Unported License ( applies to Author Choice Articles
Keywords: Bioluminescence Resonance Energy Transfer (BRET), Cell Signaling, Dimer, G Protein, G protein-Coupled Receptor (GPCR), Oligomer, Structural Biology, Super-resolution Imaging, Fluorescent Dyes, HEK293 Cells, Humans, Image Processing, Computer-Assisted, Models, Molecular, Protein Binding, Protein Conformation, Protein Multimerization, Receptors, LH, Spectrometry, Fluorescence, Spectrophotometry, Ultraviolet, Humans, Receptors, LH, Fluorescent Dyes, Spectrometry, Fluorescence, Spectrophotometry, Ultraviolet, Protein Conformation, Protein Binding, Models, Molecular, Image Processing, Computer-Assisted, Protein Multimerization, HEK293 Cells, Biochemistry & Molecular Biology, 06 Biological Sciences, 11 Medical And Health Sciences, 03 Chemical Sciences
SGUL Research Institute / Research Centre: Academic Structure > Institute of Medical & Biomedical Education (IMBE)
Academic Structure > Institute of Medical & Biomedical Education (IMBE) > Centre for Biomedical Education (INMEBE)
Journal or Publication Title: J Biol Chem
ISSN: 1083-351X
Language: eng
13 February 2015Published
16 December 2014Published Online
Publisher License: Creative Commons: Attribution 3.0
Project IDFunderFunder ID
082101/Z/07/ZWellcome Trust
BB/1008004/1Biotechnology and Biological Sciences Research Council
PubMed ID: 25516594
Web of Science ID: WOS:000349458400001
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