VPS13 proteins are proposed to function at contact sites between organelles as bridges for lipids to move directionally and in bulk between organellar membranes. VPS13s are anchored between membranes via interactions with receptors, including both peripheral and integral membrane proteins. Here we present the crystal structure of VPS13s adaptor binding domain (VAB) complexed with a Pro-X-Pro peptide recognition motif present in one such receptor, the integral membrane protein Mcp1p, and show biochemically that other Pro-X-Pro motifs bind the VAB in the same site. We further demonstrate that Mcp1p and another integral membrane protein that interacts directly with human VPS13A, XK, are scramblases. This finding supports an emerging paradigm of a partnership between bulk lipid transport proteins and scramblases. Scramblases can re-equilibrate lipids between membrane leaflets as lipids are removed from or inserted into the cytosolic leaflet of donor and acceptor organelles, respectively, in the course of protein-mediated transport.

中文翻译：

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VPS13 蛋白脂质转运的结构和生化见解


VPS13 蛋白被认为在细胞器之间的接触位点发挥作用，作为脂质在细胞器膜之间定向和大量移动的桥梁。 VPS13 通过与受体（包括外周膜蛋白和内在膜蛋白）的相互作用锚定在膜之间。在这里，我们展示了 VPS13s 接头结合域 (VAB) 与此类受体（整合膜蛋白 Mcp1p）中存在的 Pro-X-Pro 肽识别基序复合的晶体结构，并从生化角度显示其他 Pro-X-Pro 基序结合VAB 在同一站点。我们进一步证明 Mcp1p 和另一种与人 VPS13A 直接相互作用的整合膜蛋白 XK 是扰乱酶。这一发现支持了大量脂质转运蛋白和扰乱酶之间合作的新兴范例。在蛋白质介导的运输过程中，当脂质分别从供体和受体细胞器的胞质小叶中去除或插入时，扰乱酶可以重新平衡膜小叶之间的脂质。