Department of Cell Biology, University Medical Centre Utrecht, Heidelberglaan 100, Utrecht, 3584 CX, The Netherlands.
J Cell Sci. 2013 Jan 15;126(Pt 2):593-604. doi: 10.1242/jcs.115725. Epub 2012 Dec 10.
Autophagy is a conserved degradative transport pathway. It is characterized by the formation of double-membrane autophagosomes at the phagophore assembly site (PAS). Atg18 is essential for autophagy but also for vacuole homeostasis and probably endosomal functions. This protein is basically a β-propeller, formed by seven WD40 repeats, that contains a conserved FRRG motif that binds to phosphoinositides and promotes Atg18 recruitment to the PAS, endosomes and vacuoles. However, it is unknown how Atg18 association with these organelles is regulated, as the phosphoinositides bound by this protein are present on the surface of all of them. We have investigated Atg18 recruitment to the PAS and found that Atg18 binds to Atg2 through a specific stretch of amino acids in the β-propeller on the opposite surface to the FRRG motif. As in the absence of the FRRG sequence, the inability of Atg18 to interact with Atg2 impairs its association with the PAS, causing an autophagy block. Our data provide a model whereby the Atg18 β-propeller provides organelle specificity by binding to two determinants on the target membrane.
自噬是一种保守的降解运输途径。它的特征是在吞噬体组装位点 (PAS) 形成双层膜自噬体。Atg18 对自噬至关重要，但对液泡动态平衡和可能的内体功能也很重要。这种蛋白质基本上是一个由七个 WD40 重复组成的β-桨叶，其中包含一个保守的 FRRG 基序，该基序与磷酸肌醇结合，并促进 Atg18 募集到 PAS、内体和液泡。然而，目前尚不清楚 Atg18 与这些细胞器的结合是如何被调节的，因为该蛋白结合的磷酸肌醇存在于所有这些细胞器的表面。我们已经研究了 Atg18 向 PAS 的募集情况，并发现 Atg18 通过β-桨叶上 FRRG 基序对面的特定氨基酸序列与 Atg2 结合。由于 FRRG 序列缺失，Atg18 与 Atg2 相互作用的能力受损，使其与 PAS 的结合受到影响，从而导致自噬受阻。我们的数据提供了一个模型，即 Atg18β-桨叶通过与靶膜上的两个决定因素结合提供细胞器特异性。
