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Cellular Lipids Regulate the Conformational Ensembles of the Disordered Intracellular Loop 3 in β2 Adrenergic Receptor.

التفاصيل البيبلوغرافية
العنوان: Cellular Lipids Regulate the Conformational Ensembles of the Disordered Intracellular Loop 3 in β2 Adrenergic Receptor.
المؤلفون: Mukhaleva E; Irell and Manella Graduate School of Biological Sciences, Beckman Research Institute of the City of Hope, Duarte, CA, USA.; Department of Computational and Quantitative Medicine, Beckman Research Institute of the City of Hope, Duarte, CA, USA., Yang T; Irell and Manella Graduate School of Biological Sciences, Beckman Research Institute of the City of Hope, Duarte, CA, USA., Sadler F; Biochemistry, Molecular Biology and Biophysics Graduate Program, University of Minnesota, Minneapolis, MN, USA.; Department of Genetics, Cell Biology and Development, University of Minnesota, Minneapolis, MN, USA., Sivaramakrishnan S; Biochemistry, Molecular Biology and Biophysics Graduate Program, University of Minnesota, Minneapolis, MN, USA.; Department of Genetics, Cell Biology and Development, University of Minnesota, Minneapolis, MN, USA., Ma N; Irell and Manella Graduate School of Biological Sciences, Beckman Research Institute of the City of Hope, Duarte, CA, USA., Vaidehi N; Irell and Manella Graduate School of Biological Sciences, Beckman Research Institute of the City of Hope, Duarte, CA, USA.; Department of Computational and Quantitative Medicine, Beckman Research Institute of the City of Hope, Duarte, CA, USA.
المصدر: BioRxiv : the preprint server for biology [bioRxiv] 2023 Nov 29. Date of Electronic Publication: 2023 Nov 29.
نوع المنشور: Preprint
اللغة: English
بيانات الدورية: Country of Publication: United States NLM ID: 101680187 Publication Model: Electronic Cited Medium: Internet ISSN: 2692-8205 (Electronic) Linking ISSN: 26928205 NLM ISO Abbreviation: bioRxiv Subsets: PubMed not MEDLINE
مستخلص: The structurally disordered intracellular loops (ICLs) of G protein-coupled receptors (GPCRs) play a critical role in G protein coupling. In our previous work, we used a combination of FRET-based and computational methodologies to show that the third intracellular loop (ICL3) modulates the activity and G protein coupling selectivity in GPCRs. In the current study, we have uncovered the role of several lipid components in modulating the conformational ensemble of ICL3 of the β2-adrenergic receptor (β2AR). Our findings indicate that phosphatidylinositol 4,5-bisphosphate (PIP2) in the inner leaflet of the membrane bilayer acts as a stabilizing anchor for ICL3, opening the intracellular cavity to facilitate G protein coupling. This interaction between PIP2 and ICL3 causes tilting of β2AR within the cellular membrane. Notably, this tilting of the receptor is supported by ganglioside GM3 stabilizing the extracellular loops on the outer leaflet of the bilayer, thereby exerting an allosteric effect on the orthosteric ligand binding pocket. Our results underscore the significance of lipids in modulating GPCR activity, proposing an allosteric mechanism that occurs through the receptor's orientation within the membrane.
Competing Interests: Declaration of interest: The authors have no conflict of interests to declare.
التعليقات: Update in: iScience. 2024 May 23;27(6):110086. doi: 10.1016/j.isci.2024.110086. (PMID: 38947516)
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معلومات مُعتمدة: R01 GM117923 United States GM NIGMS NIH HHS; R35 GM126940 United States GM NIGMS NIH HHS; T32 AR007612 United States AR NIAMS NIH HHS
تواريخ الأحداث: Date Created: 20231211 Latest Revision: 20240710
رمز التحديث: 20240710
مُعرف محوري في PubMed: PMC10705491
DOI: 10.1101/2023.11.28.569080
PMID: 38077083
قاعدة البيانات: MEDLINE
الوصف
تدمد:2692-8205
DOI:10.1101/2023.11.28.569080