Large Arf1 guanine nucleotide exchange factors: evolution, domain structure, and roles in membrane trafficking and human disease.
Large Arf1 guanine nucleotide exchange factors: evolution, domain structure, and roles in membrane trafficking and human disease.
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DOI：
10.1007/s00438-009-0473-3
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发表时间：
2009-10
期刊：
影响因子：
--
通讯作者：
Jackson CL
中科院分区：
文献类型：
--
作者：
Bui QT;Golinelli-Cohen MP;Jackson CL
Sec7结构域的ADP核糖化因子(Arf)鸟嘌呤核苷酸交换因子(GEF)广泛存在于所有真核生物中，参与整个细胞膜的重塑过程。本文综述了Arf GEF的GBF/GEA和BIG/SEC7亚家族成员，它们都以Arf I类蛋白(Arf1-3)为底物，在内质网-高尔基体和内膜系统的转运中起着重要作用。GBF/GEA和BIG/Sec7亚家族的成员都是约200kDa的大蛋白，它们具有多个同源结构域。系统发育分析表明，Arf GEF的这两个亚家族都至少在六个真核超群中的五个中拥有成员，因此很可能在真核进化的非常早期就出现了。大的Arf1 GEF的同源结构域发挥着重要的功能作用，并参与与众多蛋白质伙伴的相互作用。大的Arf1 GEF与几种人类疾病有关。它们是几种病毒病原体复制的关键宿主因素，包括脊髓灰质炎病毒、柯萨奇病毒、小鼠肝炎冠状病毒和丙型肝炎病毒。BIG2 Arf1全环基因突变与常染色体隐性遗传性脑室周围异位症有关，这是一种神经元迁移障碍，导致大脑皮层严重畸形。了解Arf1 GEF在膜动力学中的作用对于全面了解分泌和内体途径的运输至关重要，这反过来将为人类因这些途径的调控不当而引起的疾病提供必要的见解。
The Sec7 domain ADP-ribosylation factor (Arf) guanine nucleotide exchange factors (GEFs) are found in all eukaryotes, and are involved in membrane remodeling processes throughout the cell. This review is focused on members of the GBF/Gea and BIG/Sec7 subfamilies of Arf GEFs, all of which use the class I Arf proteins (Arf1-3) as substrates, and play a fundamental role in trafficking in the endoplasmic reticulum (ER)—Golgi and endosomal membrane systems. Members of the GBF/Gea and BIG/Sec7 subfamilies are large proteins on the order of 200 kDa, and they possess multiple homology domains. Phylogenetic analyses indicate that both of these subfamilies of Arf GEFs have members in at least five out of the six eukaryotic supergroups, and hence were likely present very early in eukaryotic evolution. The homology domains of the large Arf1 GEFs play important functional roles, and are involved in interactions with numerous protein partners. The large Arf1 GEFs have been implicated in several human diseases. They are crucial host factors for the replication of several viral pathogens, including poliovirus, coxsackievirus, mouse hepatitis coronavirus, and hepatitis C virus. Mutations in the BIG2 Arf1 GEF have been linked to autosomal recessive periventricular heterotopia, a disorder of neuronal migration that leads to severe malformation of the cerebral cortex. Understanding the roles of the Arf1 GEFs in membrane dynamics is crucial to a full understanding of trafficking in the secretory and endosomal pathways, which in turn will provide essential insights into human diseases that arise from misregulation of these pathways.
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