{"title":"跨膜螺旋2中CRAC基序中的赖氨酸101赋予5 -羟色胺1a受体胆固醇诱导的热稳定性。","authors":"Parijat Sarkar, Akrati Bhat, Amitabha Chattopadhyay","doi":"10.1007/s00232-022-00262-w","DOIUrl":null,"url":null,"abstract":"<p><p>G protein-coupled receptors (GPCRs) constitute the largest class of membrane proteins that transduce signals across the plasma membrane and orchestrate a multitude of physiological processes within cells. The serotonin<sub>1A</sub> receptor is a crucial neurotransmitter receptor in the GPCR family involved in a multitude of neurological, behavioral and cognitive functions. We have previously shown, using a combination of experimental and simulation approaches, that membrane cholesterol acts as a key regulator of organization, dynamics, signaling and endocytosis of the serotonin<sub>1A</sub> receptor. In addition, we showed that membrane cholesterol stabilizes the serotonin<sub>1A</sub> receptor against thermal deactivation. In the present work, we explored the molecular basis of cholesterol-induced thermal stability of the serotonin<sub>1A</sub> receptor. For this, we explored the possible role of the K101 residue in a cholesterol recognition/interaction amino acid consensus (CRAC) motif in transmembrane helix 2 in conferring the thermal stability of the serotonin<sub>1A</sub> receptor. Our results show that a mutation in the K101 residue leads to loss in thermal stability of the serotonin<sub>1A</sub> receptor imparted by cholesterol, independent of membrane cholesterol content. We envision that our results could have potential implications in structural biological advancements of GPCRs and design of thermally stabilized receptors for drug development.</p>","PeriodicalId":50129,"journal":{"name":"Journal of Membrane Biology","volume":"255 6","pages":"739-746"},"PeriodicalIF":2.3000,"publicationDate":"2022-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"3","resultStr":"{\"title\":\"Lysine 101 in the CRAC Motif in Transmembrane Helix 2 Confers Cholesterol-Induced Thermal Stability to the Serotonin<sub>1A</sub> Receptor.\",\"authors\":\"Parijat Sarkar, Akrati Bhat, Amitabha Chattopadhyay\",\"doi\":\"10.1007/s00232-022-00262-w\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>G protein-coupled receptors (GPCRs) constitute the largest class of membrane proteins that transduce signals across the plasma membrane and orchestrate a multitude of physiological processes within cells. The serotonin<sub>1A</sub> receptor is a crucial neurotransmitter receptor in the GPCR family involved in a multitude of neurological, behavioral and cognitive functions. We have previously shown, using a combination of experimental and simulation approaches, that membrane cholesterol acts as a key regulator of organization, dynamics, signaling and endocytosis of the serotonin<sub>1A</sub> receptor. In addition, we showed that membrane cholesterol stabilizes the serotonin<sub>1A</sub> receptor against thermal deactivation. In the present work, we explored the molecular basis of cholesterol-induced thermal stability of the serotonin<sub>1A</sub> receptor. For this, we explored the possible role of the K101 residue in a cholesterol recognition/interaction amino acid consensus (CRAC) motif in transmembrane helix 2 in conferring the thermal stability of the serotonin<sub>1A</sub> receptor. Our results show that a mutation in the K101 residue leads to loss in thermal stability of the serotonin<sub>1A</sub> receptor imparted by cholesterol, independent of membrane cholesterol content. We envision that our results could have potential implications in structural biological advancements of GPCRs and design of thermally stabilized receptors for drug development.</p>\",\"PeriodicalId\":50129,\"journal\":{\"name\":\"Journal of Membrane Biology\",\"volume\":\"255 6\",\"pages\":\"739-746\"},\"PeriodicalIF\":2.3000,\"publicationDate\":\"2022-12-01\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"3\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Journal of Membrane Biology\",\"FirstCategoryId\":\"99\",\"ListUrlMain\":\"https://doi.org/10.1007/s00232-022-00262-w\",\"RegionNum\":4,\"RegionCategory\":\"生物学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q3\",\"JCRName\":\"BIOCHEMISTRY & MOLECULAR BIOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of Membrane Biology","FirstCategoryId":"99","ListUrlMain":"https://doi.org/10.1007/s00232-022-00262-w","RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q3","JCRName":"BIOCHEMISTRY & MOLECULAR BIOLOGY","Score":null,"Total":0}
Lysine 101 in the CRAC Motif in Transmembrane Helix 2 Confers Cholesterol-Induced Thermal Stability to the Serotonin1A Receptor.
G protein-coupled receptors (GPCRs) constitute the largest class of membrane proteins that transduce signals across the plasma membrane and orchestrate a multitude of physiological processes within cells. The serotonin1A receptor is a crucial neurotransmitter receptor in the GPCR family involved in a multitude of neurological, behavioral and cognitive functions. We have previously shown, using a combination of experimental and simulation approaches, that membrane cholesterol acts as a key regulator of organization, dynamics, signaling and endocytosis of the serotonin1A receptor. In addition, we showed that membrane cholesterol stabilizes the serotonin1A receptor against thermal deactivation. In the present work, we explored the molecular basis of cholesterol-induced thermal stability of the serotonin1A receptor. For this, we explored the possible role of the K101 residue in a cholesterol recognition/interaction amino acid consensus (CRAC) motif in transmembrane helix 2 in conferring the thermal stability of the serotonin1A receptor. Our results show that a mutation in the K101 residue leads to loss in thermal stability of the serotonin1A receptor imparted by cholesterol, independent of membrane cholesterol content. We envision that our results could have potential implications in structural biological advancements of GPCRs and design of thermally stabilized receptors for drug development.
期刊介绍：
The Journal of Membrane Biology is dedicated to publishing high-quality science related to membrane biology, biochemistry and biophysics. In particular, we welcome work that uses modern experimental or computational methods including but not limited to those with microscopy, diffraction, NMR, computer simulations, or biochemistry aimed at membrane associated or membrane embedded proteins or model membrane systems. These methods might be applied to study topics like membrane protein structure and function, membrane mediated or controlled signaling mechanisms, cell-cell communication via gap junctions, the behavior of proteins and lipids based on monolayer or bilayer systems, or genetic and regulatory mechanisms controlling membrane function.
Research articles, short communications and reviews are all welcome. We also encourage authors to consider publishing ''negative'' results where experiments or simulations were well performed, but resulted in unusual or unexpected outcomes without obvious explanations.
While we welcome connections to clinical studies, submissions that are primarily clinical in nature or that fail to make connections to the basic science issues of membrane structure, chemistry and function, are not appropriate for the journal. In a similar way, studies that are primarily descriptive and narratives of assays in a clinical or population study are best published in other journals. If you are not certain, it is entirely appropriate to write to us to inquire if your study is a good fit for the journal.
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