Nature Communications, 21 January, 2026, DOI：https://doi.org/10.1038/s41467-026-68679-8

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

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

Abstract

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.

Article link：https://www.nature.com/articles/s41467-026-68679-8