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Molecular evolution of a collage of cholesterol interaction motifs in transmembrane helix V of the serotonin1A receptor.
Chemistry and Physics of Lipids ( IF 3.4 ) Pub Date : 2020-08-23 , DOI: 10.1016/j.chemphyslip.2020.104955
Sarosh N Fatakia 1 , Parijat Sarkar 1 , Amitabha Chattopadhyay 1
Affiliation  

The human serotonin1A receptor is a representative member of the superfamily of G protein-coupled receptors (GPCRs) and an important drug target for neurological disorders. Using a combination of biochemical, biophysical and molecular dynamics simulation approaches, we and others have shown that membrane cholesterol modulates the organization, dynamics and function of vertebrate serotonin1A receptors. Previous studies have shown that the cytoplasmic portion of transmembrane helix V (TM V) and the extramembraneous intracellular loop 3 are critical for G-protein coupling, phosphorylation and desensitization of the receptor. We have recently resolved a collage of putative cholesterol interaction motifs from the amino acid sequence overlapping this region. In this paper, we explore the sequence plasticity of this fragment that may have adapted to altered membrane lipidome, after vertebrates evolved from primordial invertebrates. Since invertebrates have lower levels of membrane cholesterol relative to vertebrates, we compared TM V sequence fragments from invertebrate serotonin1 receptors with vertebrate orthologs to infer the sequence plasticity in TM V. We report that the average number of cholesterol interaction motifs in TM V for diverse phyla represents an increasing trend that could mirror vertebrate evolution from primordial invertebrates. By statistical modeling, we propose that the collage of cholesterol interaction motifs in TM V of the human serotonin1A receptor may have evolved from rudimentary collages, reminiscent of primordial invertebrate orthologs. Taken together, we propose that a repertoire of cholesterol-philic nonsynonymous substitutions may have enhanced collage complexity in TM V during vertebrate evolution.



中文翻译:

血清素1A受体跨膜螺旋V中的胆固醇相互作用基序拼贴的分子进化。

人血清素1A受体是G蛋白偶联受体(GPCR)超家族的代表成员,也是神经系统疾病的重要药物靶标。结合使用生物化学,生物物理和分子动力学模拟方法,我们和其他人已经表明,膜胆固醇调节脊椎动物血清素1A的组织,动力学和功能受体。先前的研究表明,跨膜螺旋V(TM V)的胞质部分和膜外细胞内环3对于受体的G蛋白偶联,磷酸化和脱敏至关重要。我们最近从重叠该区域的氨基酸序列中解析出推定的胆固醇相互作用基序的拼贴画。在本文中,我们探索了脊椎动物从原始无脊椎动物进化而来后,该片段的序列可塑性,它可能已经适应了改变的膜脂质组。由于无脊椎动物相对于脊椎动物的膜胆固醇水平较低,因此我们比较了无脊椎动物5-羟色胺1的TM V序列片段具有脊椎动物直系同源基因的受体来推断TM V中的序列可塑性。我们报道,TM V中不同种系的胆固醇相互作用基序的平均数量代表了增加的趋势,可以反映脊椎动物从原始无脊椎动物的进化。通过统计模型,我们建议人类5-羟色胺1A受体的TM V中的胆固醇相互作用基序的拼贴可能已从基本拼贴演变而来,让人联想到原始的无脊椎动物直系同源物。综上所述,我们提出,在脊椎动物进化过程中,胆固醇的非同义取代的组成可能在TM V中具有增强的拼贴复杂性。

更新日期:2020-09-14
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