Disease relevance of TRIM23

• In H1299 and A549 lung cancer cells, hARD1-silencing RNA inhibited cell proliferation and induced G(1) arrest [1].
• Addition of the 46-kDa amino-terminal extension (similarly synthesized in E. coli) to the GTP-binding ARF-domain of ARD1 enhanced GTPase activity and inhibited GDP dissociation [2].
• Down-regulation of the expression of the FIH-1 and ARD-1 genes at the transcriptional level by nickel and cobalt in the human lung adenocarcinoma A549 cell line [3].

High impact information on TRIM23

• The region containing the B-Boxes and the coiled-coil motif acts as a GTPase-activating protein for the ADP-ribosylation factor domain of ARD1 [4].
• Localization of ADP-ribosylation factor domain protein 1 (ARD1) in lysosomes and Golgi apparatus [5].
• Lysosomal and Golgi membranes isolated from human liver by immunoaffinity contained native ARD1 [5].
• Microscopic colocalization and subcellular fractionation studies showed that ARD1 was associated with the Golgi complex and lysosomal structures [5].
• We report here that ARD1 overexpressed in cells, as a fusion or nonfusion protein, is localized in vesicular structures that are concentrated mainly in the perinuclear region, but are found also throughout the cytosol [5].

Biological context of TRIM23

• ARF domain protein (ARD1), a 64-kDa GTPase with a C-terminal ADP-ribosylation factor domain, is localized to lysosomes and the Golgi apparatus [6].
• When ARD1 was used as bait to screen a human liver cDNA library using the yeast two-hybrid system, a cDNA for cytohesin-1, a approximately 50-kDa protein with ARF guanine nucleotide-exchange protein activity, was isolated [6].
• The beta-catenin binding and acetylation by hARD1 were observed in vitro [1].
• Arrest defective 1 (ARD1), an acetyltransferase, is essential for the yeast life cycle [1].
• Using ARD1 truncations, it appears that amino acids 101-190 are critical for GAP activity, whereas residues 190-333 are involved in physical interaction between the two domains of ARD1 and are required for GTP hydrolysis [7].

Anatomical context of TRIM23

• In transfected COS-7 cells, overexpressed ARD1 and cytohesin-1 were partially colocalized, as determined by confocal fluorescence microscopy [6].
• ARD1, expressed as a green fluorescent fusion protein, was initially associated with the Golgi network and subsequently appeared on lysosomes, suggesting that ARD1 might undergo vectorial transport between the two organelles [8].

Associations of TRIM23 with chemical compounds

• Association of ARD1 with the Golgi apparatus required tyrosine-based motifs [8].
• In addition, hARD1 forms protofilaments under physiological conditions of pH and temperature, as judged by electron microscopy and staining with the dyes Congo red and thioflavin T [9].
• In NB4 cells undergoing retinoic acid mediated differentiation, the level of endogenous hARD1 and NATH protein decreases while the level of hARD2 protein is stable [10].
• ARD-1, the acetyltransferase, acetylates HIF-1a at lysine 532, which enhances the interaction of HIF-1a with pVHL [3].
• Independent predictors of ARFD (n = 23) were: baseline GFR (OR 0.98, CI 0.96-0.99, p = 0.012), pulmonary diagnosis other than COPD (OR 6.80, CI 1.5-30.89, p = 0.013), mechanical ventilation > 1 d (OR 6.16, CI 1.70-22.24, p = 0.006) and parenteral amphotericin B use (OR 3.04, CI 1.03-8.98, p = 0.045) [11].

Other interactions of TRIM23

• The effector region of the ARF domain of ARD1 appeared to be critical for the specific interaction with cytohesin-1 [6].
• In agreement, cytohesin-1, but not cytohesin-2, markedly accelerated [(35)S]guanosine 5'-3-O-(thio)triphosphate binding to ARD1 [6].
• The rate of GDP dissociation from the C-terminal ARF domain in ARD1, is slowed by the adjacent 15 amino acids, which act as a GDP-dissociation inhibitor (GDI) domain [12].

Analytical, diagnostic and therapeutic context of TRIM23

• By site-specific mutagenesis it was shown that hydrophobic amino acids in this region were particularly important in stabilizing the GDP-bound form of ARD1 [13].
• Structural characterization of native hARD1 using size exclusion chromatography, circular dichroism, and fluorescence spectroscopy shows the protein consists of a compact globular region comprising two thirds of the protein and a flexible unstructured C terminus [9].
• Cells were transiently transfected with HIF-1alpha mutant and antisense arrest-defective 1 protein (ARD-1), and HIF-1alpha acetylation was assayed by immunoprecipitation [14].
• Both ARFnD and ARFD were associated with longer duration of mechanical ventilation, increased hospital stay and increased early mortality [11].

References