VAP, a Versatile Access Point for the Endoplasmic Reticulum: Review and analysis of FFAT-like motifs in the VAPome
VAP, a Versatile Access Point for the Endoplasmic Reticulum: Review and analysis of FFAT-like motifs in the VAPome
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DOI：
10.1016/j.bbalip.2016.02.009
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发表时间：
2016-08-01
影响因子：
4.8
通讯作者：
Levine, Tim P.
中科院分区：
文献类型：
--
作者：
Murphy, Sarah E.;Levine, Tim P.
VAMP相关蛋白（VAP）的功能障碍与神经退行性疾病（肌萎缩侧索硬化症和帕金森病）有关。在这里，我们总结了什么是已知的VAP在人类和模式生物的细胞内相互作用。VAP是位于内质网（ER）胞质面的一种简单、小且高度保守的蛋白质。它是细胞器上唯一的蛋白质，作为细胞质蛋白质的受体。这可以解释VAP的相互作用伙伴的范围非常广泛，许多细胞途径的成分结合它进入ER。许多结合VAP的蛋白质也靶向其他细胞内膜，因此VAP是ER和其他细胞器之间膜接触位点的多个分子桥的组成部分。到目前为止，已经在VAP相互作用组（VAPome）中鉴定了大约100种蛋白质，其中一小部分具有如其最初定义的“酸性区中的两个苯丙氨酸”（FEAT）基序。我们使用一种简单的算法分析了人类和酵母中的整个VAPome，该算法识别了更多的FFAT样基序。我们表明，大约50%的VAPome通过VAP-FFAT相互作用直接或间接结合。我们还审查了VAP遗传性疾病的发病机制的证据，这似乎是由于整体VAP水平降低，导致ER应激。不可能确定一种单一的相互作用是疾病的基础。这篇文章是由Tim P. Levine和Anant K.梅农(C)© 2016 Elsevier B. V.版权所有。
Dysfunction of VAMP-associated protein (VAP) is associated with neurodegeneration, both Amyotrophic Lateral Sclerosis and Parkinson's disease. Here we summarize what is known about the intracellular interactions of VAP in humans and model organisms. VAP is a simple, small and highly conserved protein on the cytoplasmic face of the endoplasmic reticulum (ER). It is the sole protein on that large organelle that acts as a receptor for cytoplasmic proteins. This may explain the extremely wide range of interacting partners of VAP, with components of many cellular pathways binding it to access the ER. Many proteins that bind VAP also target other intracellular membranes, so VAP is a component of multiple molecular bridges at membrane contact sites between the ER and other organelles. So far approximately 100 proteins have been identified in the VAP interactome (VAPome), of which a small minority have a "two phenylalanines in an acidic tract" (FEAT) motif as it was originally defined. We have analyzed the entire VAPome in humans and yeast using a simple algorithm that identifies many more FFAT-like motifs. We show that approximately 50% of the VAPome binds directly or indirectly via the VAP-FFAT interaction. We also review evidence on pathogenesis in genetic disorders of VAP, which appear to arise from reduced overall VAP levels, leading to ER stress. It is not possible to identify one single interaction that underlies disease. This article is part of a Special Issue entitled: The cellular lipid landscape edited by Tim P. Levine and Anant K. Menon. (C) 2016 Elsevier B.V. All rights reserved.