An Ancient CFTR Ortholog Informs Molecular Evolution in ABC Transporters.,Developmental Cell

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An Ancient CFTR Ortholog Informs Molecular Evolution in ABC Transporters.
Developmental Cell ( IF 10.7 ) Pub Date : 2019-10-31 , DOI: 10.1016/j.devcel.2019.09.017
Guiying Cui ₁ , Jeong Hong ₂ , Yu-Wen Chung-Davidson ₃ , Daniel Infield ₄ , Xin Xu ₅ , Jindong Li ₅ , Luba Simhaev ₆ , Netaly Khazanov ₆ , Brandon Stauffer ₁ , Barry Imhoff ₁ , Kirsten Cottrill ₁ , J Edwin Blalock ₇ , Weiming Li ₃ , Hanoch Senderowitz ₆ , Eric Sorscher ₂ , Nael A McCarty ₁ , Amit Gaggar ₅

Affiliation

Department of Pediatrics and Children's Healthcare of Atlanta, Center for Cystic Fibrosis and Airways Disease Research, Emory University, Atlanta, GA 30322, USA.
Department of Pediatrics and Children's Healthcare of Atlanta, Center for Cystic Fibrosis and Airways Disease Research, Emory University, Atlanta, GA 30322, USA; Department of Medicine, Gregory Fleming James Cystic Fibrosis Research Center, and Program in Protease and Matrix Biology, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
Department of Fisheries and Wildlife, Michigan State University, East Lansing, MI 48823, USA.
Department of Pediatrics and Children's Healthcare of Atlanta, Center for Cystic Fibrosis and Airways Disease Research, Emory University, Atlanta, GA 30322, USA; Department of Molecular Physiology and Biophysics, University of Iowa, Iowa City, IA 52242, USA.
Department of Medicine, Gregory Fleming James Cystic Fibrosis Research Center, and Program in Protease and Matrix Biology, University of Alabama at Birmingham, Birmingham, AL 35294, USA; Birmingham Veterans Administration Medical Center, Birmingham, AL 35233, USA.
Department of Chemistry, Bar-Ilan University, Ramat Gan, Israel.
Department of Medicine, Gregory Fleming James Cystic Fibrosis Research Center, and Program in Protease and Matrix Biology, University of Alabama at Birmingham, Birmingham, AL 35294, USA.

The cystic fibrosis transmembrane conductance regulator (CFTR) is a chloride channel central to the development of secretory diarrhea and cystic fibrosis. The oldest CFTR ortholog identified is from dogfish shark, which retains similar structural and functional characteristics to the mammalian protein, thereby highlighting CFTR's critical role in regulating epithelial ion transport in vertebrates. However, the identification of an early CFTR ortholog with altered structure or function would provide critical insight into the evolution of epithelial anion transport. Here, we describe the earliest known CFTR, expressed in sea lamprey (Petromyzon marinus), with unique structural features, altered kinetics of activation and sensitivity to inhibition, and altered single-channel conductance compared to human CFTR. Our data provide the earliest evolutionary evidence of CFTR, offering insight regarding changes in gene and protein structure that underpin evolution from transporter to anion channel. Importantly, these data provide a unique platform to enhance our understanding of vertebrate phylogeny over a critical period of evolutionary expansion.

中文翻译：

古老的 CFTR 直向同源物告知 ABC 转运蛋白的分子进化。

囊性纤维化跨膜电导调节剂 (CFTR) 是一种氯离子通道，是分泌性腹泻和囊性纤维化发展的核心。鉴定出的最古老的 CFTR 直向同源物来自角鲨，它保留了与哺乳动物蛋白质相似的结构和功能特征，从而突出了 CFTR 在调节脊椎动物上皮离子转运中的关键作用。然而，识别具有改变结构或功能的早期 CFTR 直向同源物将为上皮阴离子转运的演变提供重要的洞察力。在这里，我们描述了已知最早的 CFTR，在海七鳃鳗（Petromyzon marinus）中表达，与人类 CFTR 相比，它具有独特的结构特征、活化动力学和抑制敏感性的改变以及单通道电导的改变。我们的数据提供了 CFTR 最早的进化证据，提供了关于支持从转运蛋白到阴离子通道进化的基因和蛋白质结构变化的见解。重要的是，这些数据提供了一个独特的平台，以增强我们在进化扩张的关键时期对脊椎动物系统发育的理解。

更新日期：2019-11-01

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