Lysine 101 in the CRAC Motif in Transmembrane Helix 2 Confers Cholesterol-Induced Thermal Stability to the Serotonin1A Receptor.

IF 2.3 4区 生物学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY
Parijat Sarkar, Akrati Bhat, Amitabha Chattopadhyay
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引用次数: 3

Abstract

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.

Abstract Image

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。
G蛋白偶联受体(gpcr)是最大的一类膜蛋白,它可以传递跨质膜的信号,并协调细胞内的多种生理过程。5 -羟色胺1a受体是GPCR家族中重要的神经递质受体,参与多种神经、行为和认知功能。我们之前已经通过实验和模拟相结合的方法表明,膜胆固醇在5 -羟色胺1a受体的组织、动力学、信号传导和内吞作用中起着关键的调节作用。此外,我们发现膜胆固醇稳定了5 -羟色胺1a受体,防止热失活。在目前的工作中,我们探索了胆固醇诱导的5 -羟色胺1a受体热稳定性的分子基础。为此,我们探索了K101残基在跨膜螺旋2中胆固醇识别/相互作用氨基酸共识(CRAC)基序中赋予5 -羟色胺1a受体热稳定性的可能作用。我们的研究结果表明,K101残基的突变导致胆固醇传递的5 -羟色胺1a受体的热稳定性丧失,与膜胆固醇含量无关。我们设想我们的结果可能对gpcr的结构生物学进步和药物开发热稳定受体的设计具有潜在的意义。
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来源期刊
Journal of Membrane Biology
Journal of Membrane Biology 生物-生化与分子生物学
CiteScore
4.80
自引率
4.20%
发文量
63
审稿时长
6-12 weeks
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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