title: Structural Insights into Arl1-Mediated Targeting of the Arf-GEF BIG1 to the trans-Golgi.
abstract: The GTPase Arf1 is the major regulator of vesicle traffic at both the cis- and trans-Golgi. Arf1 is activated at the cis-Golgi by the guanine nucleotide exchange factor (GEF) GBF1 and at the trans-Golgi by the related GEF BIG1 or its paralog, BIG2. The trans-Golgi-specific targeting of BIG1 and BIG2 depends on the Arf-like GTPase Arl1. We find that Arl1 binds to the dimerization and cyclophilin binding (DCB) domain in BIG1 and report a crystal structure of human Arl1 bound to this domain. Residues in the DCB domain that bind Arl1 are required for BIG1 to locate to the Golgi in vivo. DCB domain-binding residues in Arl1 have a distinct conformation from those in known Arl1-effector complexes, and this plasticity allows Arl1 to interact with different effectors of unrelated structure. The findings provide structural insight into how Arf1 GEFs, and hence active Arf1, achieve their correct subcellular distribution.
authors.affiliation: MRC Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge CB2 0QH, UK.
authors.forename: Antonio
authors.initials: A
authors.lastname: Galindo
authors.affiliation: MRC Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge CB2 0QH, UK.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Soler
authors.affiliation: MRC Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge CB2 0QH, UK.
authors.forename: Stephen H
authors.initials: SH
authors.lastname: McLaughlin
authors.affiliation: MRC Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge CB2 0QH, UK.
authors.forename: Minmin
authors.initials: M
authors.lastname: Yu
authors.affiliation: MRC Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge CB2 0QH, UK.
authors.forename: Roger L
authors.initials: RL
authors.lastname: Williams
authors.affiliation: MRC Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge CB2 0QH, UK. Electronic address: sean@mrc-lmb.cam.ac.uk.
authors.forename: Sean
authors.initials: S
authors.lastname: Munro
mesh_terms: D020823:ADP-Ribosylation Factor 1 / Q000378:metabolism*; D020727:ADP-Ribosylation Factors / Q000378:metabolism*; D000595:Amino Acid Sequence; D001665:Binding Sites; D045744:Cell Line, Tumor; D021983:Cyclophilins / Q000378:metabolism; D019281:Dimerization; D020558:GTP Phosphohydrolases / Q000378:metabolism; D006056:Golgi Apparatus / Q000378:metabolism*; D020662:Guanine Nucleotide Exchange Factors / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism*; D000072417:Protein Domains; D016415:Sequence Alignment
chemical_list: C119087:ARFGEF1 protein, human; C119088:ARFGEF2 protein, human; D020662:Guanine Nucleotide Exchange Factors; D008565:Membrane Proteins; C097313:ADP-ribosylation factor related proteins; D020558:GTP Phosphohydrolases; D020823:ADP-Ribosylation Factor 1; D020727:ADP-Ribosylation Factors; D021983:Cyclophilins