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TitleStructural basis for the dynamic conformations of AP-4 and its association with ARF1.
Journal, issue, pagesNat Commun, Vol. 17, Issue 1, Year 2026
Publish dateJan 21, 2026
AuthorsYanghui Wang / Wei Li / Yunlong Qiu / Si Wu / Liu Hong / Yan Zhao / Wei Feng /
PubMed AbstractAmong 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 ...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.
External linksNat Commun / PubMed:41565640 / PubMed Central
MethodsEM (single particle)
Resolution4.0 - 6.8 Å
Structure data

EMDB-63965, PDB-9u9i:
M4-CTD-undocked AP-4 core in apo form
Method: EM (single particle) / Resolution: 4.0 Å

EMDB-63966, PDB-9u9j:
M4-CTD-docked AP-4 core in apo form
Method: EM (single particle) / Resolution: 4.2 Å

EMDB-63968, PDB-9u9r:
ARF1(Q71L) bound M4-CTD-undocked AP-4 core
Method: EM (single particle) / Resolution: 6.6 Å

EMDB-63969, PDB-9u9s:
ARF1(Q71L) bound M4-CTD-docked AP-4 core
Method: EM (single particle) / Resolution: 6.8 Å

Source
  • homo sapiens (human)
KeywordsPROTEIN TRANSPORT / adaptor protein complex / cargo transportation / AP-4 complex / TRANSPORT PROTEIN

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