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首页> 外文期刊>Journal of Molecular Biology >Co-Translational Folding of the First Transmembrane Domain of ABC-Transporter CFTR is Supported by Assembly with the First Cytosolic Domain
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Co-Translational Folding of the First Transmembrane Domain of ABC-Transporter CFTR is Supported by Assembly with the First Cytosolic Domain

机译：通过组装与第一细胞溶质结构域的组装支持第一跨膜结构域的第一跨膜结构域的共转化折叠

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摘要

ABC transporters transport a wealth of molecules across membranes and consist of transmembrane and cytosolic domains. Their activity cycle involves a tightly regulated and concerted domain choreography. Regulation is driven by the cytosolic domains and function by the transmembrane domains. Folding of these polytopic multidomain proteins to their functional state is a challenge for cells, which is mitigated by co-translational and sequential events. We here reveal the first stages of co-translational domain folding and assembly of CFTR, the ABC transporter defective in the most abundant rare inherited disease cystic fibrosis. We have combined biosynthetic radiolabeling with protease-susceptibility assays and domain-specific antibodies. The most N-terminal domain, TMD1 (transmembrane domain 1), folds both its hydrophobic and soluble helices during translation: the transmembrane helices pack tightly and the cytosolic N- and C-termini assemble with the first cytosolic helical loop ICL1, leaving only ICL2 exposed. This N-C-ICL1 assembly is strengthened by two independent events: (i) assembly of ICL1 with the N-terminal subdomain of the next domain, cytosolic NBD1 (nucleotide-binding domain 1); and (ii) in the presence of corrector drug VX-809, which rescues cell-surface expression of a range of disease-causing CFTR mutants. Both lead to increased shielding of the CFTR N-terminus, and their additivity implies different modes of action. Early assembly of NBD1 and TMD1 is essential for CFTR folding and positions both domains for the required assembly with TMD2. Altogether, we have gained insights into this first, nucleating, VX-809-enhanced domain-assembly event during and immediately after CFTR translation, involving structures conserved in type-I ABC exporters. (C) 2021 The Author(s). Published by Elsevier Ltd.
机译：ABC转运蛋白跨膜转运大量分子，由跨膜和胞质结构域组成。他们的活动周期涉及一个严格控制和协调的领域编排。调控由胞质结构域驱动，功能由跨膜结构域驱动。将这些多面体多结构域蛋白质折叠到其功能状态对细胞来说是一个挑战，共翻译和顺序事件可以缓解这一挑战。我们在此揭示了CFTR共翻译结构域折叠和组装的第一阶段，CFTR是一种ABC转运蛋白，在最丰富的罕见遗传性疾病囊性纤维化中存在缺陷。我们将生物合成放射性标记与蛋白酶敏感性分析和领域特异性抗体相结合。最具N端结构域TMD1（跨膜结构域1）在翻译过程中折叠其疏水螺旋和可溶性螺旋：跨膜螺旋紧密堆积，胞质N端和C端与第一个胞质螺旋环ICL1组装，只留下ICL2暴露。这种N-C-ICL1组装通过两个独立的事件得到加强：（i）ICL1与下一个结构域的N-末端子域，胞浆NBD1（核苷酸结合结构域1）的组装；以及（ii）在存在校正药物VX-809的情况下，该药物拯救了一系列致病性CFTR突变体的细胞表面表达。两者都会增加CFTR N-末端的屏蔽，它们的相加性意味着不同的作用模式。NBD1和TMD1的早期组装对于CFTR折叠至关重要，并将这两个域定位到所需的TMD2组装中。总之，我们在CFTR翻译期间和翻译后立即深入了解了这一首次成核的VX-809增强型结构域组装事件，涉及I型ABC导出器中保存的结构。（c）2021作者。爱思唯尔有限公司出版。

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