Mechanistic Insights into Regulated Cargo Binding by ACAP1 Protein
Mechanistic Insights into Regulated Cargo Binding by ACAP1 Protein
复制标题
ACAP1 蛋白调节货物结合的机制见解
DOI：
10.1074/jbc.m112.378810
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发表时间：
2012-08-17
影响因子：
4.8
通讯作者：
Hsu, Victor W.
中科院分区：
文献类型：
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作者：
Bai, Ming;Pang, Xiaoyun;Hsu, Victor W.
衣壳复合物将蛋白质货物分类进入囊泡运输途径。一类新兴的外壳成分是作用于小gtpase的adp -核糖基化因子（ARF）家族的gtpase激活蛋白（GAPs）。ACAP1 （ArfGAP具有卷曲线圈、锚蛋白重复和PH结构域蛋白1）是ARF6 GAP，也是最近定义的用于内吞循环的网格蛋白复合物的关键组分。Akt的磷酸化已被证明可以增强ACAP1的货物结合，这解释了整合素回收是一个受调节运输的例子。我们现在对ACAP1在货物绑定水平上如何实现这一调节的机制有了进一步的了解。我们最初在ACAP1识别的整合素β 1的细胞质结构域中定义了一个关键序列，并表明该序列可作为回收分类信号。然后，我们进行了结构、建模和功能研究的结合，表明ACAP1的磷酸化缓解了调节货物结合的局部自抑制机制。因此，我们阐明了控制整合素回收的关键监管节点，并进一步了解了受管制的货物绑定如何导致受管制的运输。
Coat complexes sort protein cargoes into vesicular transport pathways. An emerging class of coat components has been the GTPase-activating proteins (GAPs) that act on the ADP-ribosylation factor (ARF) family of small GTPases. ACAP1 (ArfGAP with coiled-coil, ankyrin repeat, and PH domains protein 1) is an ARF6 GAP that also acts as a key component of a recently defined clathrin complex for endocytic recycling. Phosphorylation by Akt has been shown to enhance cargo binding by ACAP1 in explaining how integrin recycling is an example of regulated transport. We now shed further mechanistic insights into how this regulation is achieved at the level of cargo binding by ACAP1. We initially defined a critical sequence in the cytoplasmic domain of integrin beta 1 recognized by ACAP1 and showed that this sequence acts as a recycling sorting signal. We then pursued a combination of structural, modeling, and functional studies, which suggest that phosphorylation of ACAP1 relieves a localized mechanism of autoinhibition in regulating cargo binding. Thus, we have elucidated a key regulatory juncture that controls integrin recycling and also advanced the understanding of how regulated cargo binding can lead to regulated transport.