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<p>During macroautophagy, the de novo formation of the autophagosome at a membrane contact site (MCS) with the endoplasmic reticulum requires directional lipid flux for the growth of the initial phagophore before its sealing into an autophagosome and subsequent fusion with the lysosome/vacuole. It remains unclear, however, how the formation of this specialized MCS and the directionality of the lipid flux are controlled. Here, we present the structure of the key lipid transfer protein Atg2 from yeast solved together with its Atg18 binding partner, a phosphatidylinositol-3-phosphate (PtdIns3P) effector, using cryo-electron microscopy. We reveal a new interface in Atg2 that, together with PtdIns3P, is required for Atg18 recruitment and lipid transfer activity. Furthermore, we visualize lipid densities along the internal hydrophobic cavity of Atg2, providing structural evidence that Atg2 cavity is filled with lipids throughout the entire length, even when Atg2 is cytosolic. Finally, molecular dynamics simulations show that the complex generates membrane curvature, efficiently positioning the lipid channel of Atg2 towards the membrane to promote lipid transfer into the elongating phagophore.</p>

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Atg18 interaction positions Atg2 for efficient lipid transfer into phagophore elongation

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年5月20日

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  • Sabrina Chumpen Ramirez,
  • Dmitry Shvarev,
  • Prado Vargas Duarte,
  • Yara Ahmed,
  • Jana Milach,
  • Emma Lang,
  • Stefan Kuchenbuch,
  • Stefano Vanni,
  • Fulvio Reggiori,
  • Arne Moeller,
  • Christian Ungermann

摘要

During macroautophagy, the de novo formation of the autophagosome at a membrane contact site (MCS) with the endoplasmic reticulum requires directional lipid flux for the growth of the initial phagophore before its sealing into an autophagosome and subsequent fusion with the lysosome/vacuole. It remains unclear, however, how the formation of this specialized MCS and the directionality of the lipid flux are controlled. Here, we present the structure of the key lipid transfer protein Atg2 from yeast solved together with its Atg18 binding partner, a phosphatidylinositol-3-phosphate (PtdIns3P) effector, using cryo-electron microscopy. We reveal a new interface in Atg2 that, together with PtdIns3P, is required for Atg18 recruitment and lipid transfer activity. Furthermore, we visualize lipid densities along the internal hydrophobic cavity of Atg2, providing structural evidence that Atg2 cavity is filled with lipids throughout the entire length, even when Atg2 is cytosolic. Finally, molecular dynamics simulations show that the complex generates membrane curvature, efficiently positioning the lipid channel of Atg2 towards the membrane to promote lipid transfer into the elongating phagophore.