货物结合促进哺乳动物细胞表面的KDEL受体聚集
Cargo binding promotes KDEL receptor clustering at the mammalian cell surface
摘要：
跨膜受体聚集是原核细胞和真核细胞中普遍存在的现象，以物理地感知受体/配体相互作用并随后将外源信号翻译成细胞应答。尽管已经描述了多种受体的受体簇形成，从细菌中的趋化性受体到哺乳动物细胞中的生长因子和神经递质受体，但对潜在分子过程的机械理解仍然令人困惑。为了填补这一空白，我们采用了实验和理论相结合的方法，在与模型货物/配体相互作用后，在哺乳动物细胞表面解剖和调节由KDEL受体（KDELRs）介导的货物结合、内化和细胞应答。使用蓖麻毒素A链的荧光变体作为KDELR-配体，eGFP-RTA（H/KDEL），我们证明货物结合诱导剂量依赖性受体簇的形成和随后的内化从膜，这是相关的，并抵消了顺行和微管辅助受体转运到质膜上的首选停靠位点。通过分析参数和广泛的数值模拟，我们表明，货物同步受体运输从和到膜是导致KDELR/货物簇形成在哺乳动物细胞表面。
英文摘要：
Transmembrane receptor clustering is a ubiquitous phenomenon in pro- and eukaryotic cells to physically sense receptor/ligand interactions and subsequently translate an exogenous signal into a cellular response. Despite that receptor cluster formation has been described for a wide variety of receptors, ranging from chemotactic receptors in bacteria to growth factor and neurotransmitter receptors in mammalian cells, a mechanistic understanding of the underlying molecular processes is still puzzling. In an attempt to fill this gap we followed a combined experimental and theoretical approach by dissecting and modulating cargo binding, internalization and cellular response mediated by KDEL receptors (KDELRs) at the mammalian cell surface after interaction with a model cargo/ligand. Using a fluorescent variant of ricin toxin A chain as KDELR-ligand, eGFP-RTA (H/KDEL), we demonstrate that cargo binding induces dose-dependent receptor cluster formation at and subsequent internalization from the membrane which is associated and counteracted by anterograde and microtubule-assisted receptor transport to preferred docking sites at the plasma membrane. By means of analytical arguments and extensive numerical simulations we show that cargo-synchronized receptor transport from and to the membrane is causative for KDELR/cargo cluster formation at the mammalian cell surface.
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