Large Arf1 guanine nucleotide exchange factors: evolution,domain structure,and roles in membrane trafficking and human disease |
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Authors: | Quynh Trang Bui Marie-Pierre Golinelli-Cohen Catherine L Jackson |
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Institution: | (1) Laboratoire d’Enzymologie et Biochimie Structurales, Bat 34, CNRS, 1, Avenue de la Terrasse, 91198 Gif-sur-Yvette, France;(2) Present address: Laboratoire de Biologie Cellulaire, Institut Jean-Pierre Bourgin, INRA, 78026 Versailles, France; |
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Abstract: | 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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