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<p>Among the distinct adaptor protein (AP) complexes, AP-4 primarily functions as a non-clathrin-coated vesicle machinery essential for intracellular membrane trafficking. ARF1 is a master regulator of AP-4 membrane recruitment, but the underlying mechanism remains elusive. Here, we present the cryo-EM structures of soluble AP-4 and the AP-4/ARF1 complex. Unexpectedly, AP-4 adopts a dynamic equilibrium between closed and open conformations, caused by loose contacts between its medium subunit and central core. ARF1 binding induces only subtle changes in AP-4, which retains its conformational equilibrium. Mutations at the AP-4/ARF1 interface disrupt complex formation and impair ARF1-dependent membrane recruitment. Efficient membrane recruitment of AP-4 likely requires the synergistic engagement of ARF1 and cargoes. Disrupting the conformational flexibility of AP-4 interferes with this synergistic effect and compromises AP-4-mediated membrane trafficking. Our findings may redefine AP-4 as a conformationally dynamic complex modulated by cooperative interactions, providing insights into neurodevelopmental disorders associated with AP-4 dysfunction.</p>

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Structural basis for the dynamic conformations of AP-4 and its association with ARF1

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年1月21日

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  • Yanghui Wang,
  • Wei Li,
  • Yunlong Qiu,
  • Si Wu,
  • Liu Hong,
  • Yan Zhao,
  • Wei Feng

摘要

Among the distinct adaptor protein (AP) complexes, AP-4 primarily functions as a non-clathrin-coated vesicle machinery essential for intracellular membrane trafficking. ARF1 is a master regulator of AP-4 membrane recruitment, but the underlying mechanism remains elusive. Here, we present the cryo-EM structures of soluble AP-4 and the AP-4/ARF1 complex. Unexpectedly, AP-4 adopts a dynamic equilibrium between closed and open conformations, caused by loose contacts between its medium subunit and central core. ARF1 binding induces only subtle changes in AP-4, which retains its conformational equilibrium. Mutations at the AP-4/ARF1 interface disrupt complex formation and impair ARF1-dependent membrane recruitment. Efficient membrane recruitment of AP-4 likely requires the synergistic engagement of ARF1 and cargoes. Disrupting the conformational flexibility of AP-4 interferes with this synergistic effect and compromises AP-4-mediated membrane trafficking. Our findings may redefine AP-4 as a conformationally dynamic complex modulated by cooperative interactions, providing insights into neurodevelopmental disorders associated with AP-4 dysfunction.