Disease relevance of ARL1

• Purified hARL1 (rARL1) synthesized in Escherichia coli had less activity toward PLD than did rARF1, although PLD activation by both proteins was guanosine guanosine 5'-(gamma-thio)triphosphate (GTPgammaS)-dependent [1].
• Expression of an ADP-ribosylation factor like gene, ARF4L, is induced after transient forebrain ischemia in the gerbil [2].

High impact information on ARL1

• Structural basis for Arl1-dependent targeting of homodimeric GRIP domains to the Golgi apparatus [3].
• The Arf-like GTPase Arl1 regulates the translocation of GRIP domain-containing golgins to Golgi membranes [3].
• Experiments using these altered forms of Arl2 in vitro and in vivo demonstrate that it is GDP-bound Arl2 that interacts with cofactor D, thereby averting tubulin and microtubule destruction [4].
• Comparative genomic analysis identifies an ADP-ribosylation factor-like gene as the cause of Bardet-Biedl syndrome (BBS3) [5].
• The function of ARFRP1 is unknown, but mammalian ARL1 has recently been found to interact with a number of effectors including the GRIP domain that is present in a family of Golgi-localized long coiled-coil proteins [6].

Biological context of ARL1

• Although ARF-like (ARL) proteins are very similar in sequence to ARFs, they were initially believed not to activate CT or PLD. mRNA for human ARL1 (hARL1), which is 57% identical in amino acid sequence to hARF1, is present in all tissues, with the highest amounts in kidney and pancreas and barely detectable amounts in brain [1].
• Cbs undergoes a dramatic relocalization during mitosis from the cytoplasm to an association with chromosomes from late prometaphase to early telophase, by a transport mechanism that requires the GRIP domain and Arl1, the product of the Arf72A locus [7].
• Genetic analysis in a number of species has shown that Arl1 is not essential for exocytosis, but rather suggest that it is required for traffic from endosomes to the Golgi [8].
• RNA interference of ARL1 in procyclic cells has no effect on parasite growth or morphology [9].
• Prior to cell death, depletion of ARL1 protein in bloodstream parasites results in abnormal morphology, including disintegration of the Golgi structure, multiple flagella and nuclei, and the presence of large numbers of vesicles [9].

Anatomical context of ARL1

• Like ARFs and ARL1, the binding of SCOCO to Golgi membranes is rapidly reversed by brefeldin A, suggesting the presence of a brefeldin A-sensitive ARL1 exchange factor [10].
• LdARL-3A, a Leishmania promastigote-specific ADP-ribosylation factor-like protein, is essential for flagellum integrity [11].
• Arl2 specifically prevents destruction of tubulin and microtubules by cofactor D, but not by cofactor E. We generated mutant forms of Arl2 based on the known properties of classical Ras-family mutations [4].
• Arl1p is involved in transport of the GPI-anchored protein Gas1p from the late Golgi to the plasma membrane [12].
• Photoreceptor synaptic protein HRG4 (UNC119) interacts with ARL2 via a putative conserved domain [13].

Associations of ARL1 with chemical compounds

• Before cell death, depletion of ARL1 protein results in disintegration of the Golgi structure and a delay in exocytosis of the abundant GPI (glycosylphosphatidylinositol)-anchored VSG (variant surface glycoprotein) to the parasite surface [14].

Other interactions of ARL1

• To determine whether different structural elements are responsible for the activation structural elements are responsible for the activation of the A subunit of cholera toxin and PLD, chimeric proteins were constructed by switching the amino-terminal 73 amino acids of ARF1 and ARL1 [15].
• Specific interactions between ARL1 and two binding proteins, SCOCO and Golgin-245, are defined and characterized in more detail [10].
• The ARF-like GTPases Arl1p and Arl3p act in a pathway that interacts with vesicle-tethering factors at the Golgi apparatus [6].
• Golgin-97 and Golgin-245 are dissociated from the Golgi when Arl1 is knocked-down by its siRNA [16].
• Two recent papers show that the Arl3p and Arl1p small GTPases act sequentially to recruit GRIP domain proteins to the Golgi [17].

Analytical, diagnostic and therapeutic context of ARL1

• A novel antibody directed against common parts of the hARLPs revealed hARLP reactivity in human HCC by immunohistochemistry [18].
• The interaction of ARL2 with HRG4 was further confirmed by co-immunoprecipitation and direct binding analysis [13].
• The presence of ARL2 in the retina and co-localization with HRG4 was confirmed by Western blot and double immunofluorescence analysis, respectively [13].

References