Targeting of the Arf-GEF GBF1 to lipid droplets and Golgi membranes

Bouvet, Samuel; Golinelli-Cohen, Marie-Pierre; Contremoulins, Vincent; Jackson, Catherine

doi:10.1242/jcs.134254

Cited by 71 publications

(90 citation statements)

References 45 publications

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“…The HDS1 domain of human GBF1 bound directly to "Golgi-mix" liposomes and to artificial lipid droplets, and this interaction was inhibited in a construct comprising both the Sec7 and HDS1 domains. 40 Consistent with the inhibition of membranebinding elements in the HDS1 domain by the Sec7 domain, a yeast Sec7 construct encompassing the DCB-HUS-Sec7-HDS1 domains did not bind autonomously to membranes, yet it was about 5-fold more active on membranes than the shorter DCB-HUS-Sec7 construct. 41 These studies are consistent with a mechanism Table 1.…”

Section: Regulation Of Large Arfgefs By Direct and Small Gtpase-mediamentioning

confidence: 58%

“…41 BIG1 and BIG2 (the mammalian orthologs of Sec7) also interacted with Arf-GTP in cells, but the region critical for interaction was mapped to the N-terminal DCB-HUS domains. 39 Interaction with Arf-GTP was not observed for yeast Gea1, which belongs to the other large ArfGEF subfamily 41 or for its human ortholog GBF1, 40 suggesting that it is specific to the Sec7/BIG subfamily. Other GTP-bound small GTPases have been reported to interact with large ArfGEFs and to regulate their localization and/or activities.…”

Section: Regulation Of Large Arfgefs By Direct and Small Gtpase-mediamentioning

confidence: 98%

“…Consistent with our study, the DCB-HUS domains are required for the association of mammalian BIG1 and BIG2 to the TGN 39 and of human GBF1, which belongs to the other subfamily of large ArfGEFs, to the Golgi. 40 In a contrasting set of experiments, a yeast Sec7 construct carrying the DCB-HUS-Sec7 domains did not bind to membranes autonomously and was 3-4-fold less active on membranes than in solution. 38,41 This construct was however about 4-fold more active on membranes than the Sec7 domain and this led to a model in which it was proposed to assist in the displacement of the N-terminal helix of Arf.…”

Section: Regulation Of Large Arfgefs By Direct and Small Gtpase-mediamentioning

confidence: 98%

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Allosteric regulation of Arf GTPases and their GEFs at the membrane interface

2016

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Arf GTPases assemble protein complexes on membranes to carry out major functions in cellular traffic. An essential step is their activation by guanine nucleotide exchange factors (GEFs), whose Sec7 domain stimulates GDP/GTP exchange. ArfGEFs form 2 major families: ArfGEFs with DCB, HUS and HDS domains (GBF1 and BIG1/BIG2 in humans), which act at the Golgi; and ArfGEFs with a Cterminal PH domain (cytohesin, EFA6 and BRAG), which function at the plasma membrane and endosomes. In addition, pathogenic bacteria encode an ArfGEF with a unique membrane-binding domain. Here we review the allosteric regulation of Arf GTPases and their GEFs at the membrane interface. Membranes contribute several regulatory layers: at the GTPase level, where activation by GTP is coupled to membrane recruitment by a built-in structural device; at the Sec7 domain, which manipulates this device to ensure that Arf-GTP is attached to membranes; and at the level of noncatalytic ArfGEF domains, which form direct or GTPase-mediated interactions with membranes that enable a spectacular diversity of regulatory regimes. Notably, we show here that membranes increase the efficiency of a large ArfGEF (human BIG1) by 32-fold by interacting directly with its Nterminal DCB and HUS domains. The diversity of allosteric regulatory regimes suggests that ArfGEFs can function in cascades and circuits to modulate the shape, amplitude and duration of Arf signals in cells. Because Arf-like GTPases feature autoinhibitory elements similar to those of Arf GTPases, we propose that their activation also requires allosteric interactions of these elements with membranes or other proteins.

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Section: Regulation Of Large Arfgefs By Direct and Small Gtpase-mediamentioning

confidence: 58%

Section: Regulation Of Large Arfgefs By Direct and Small Gtpase-mediamentioning

confidence: 98%

Section: Regulation Of Large Arfgefs By Direct and Small Gtpase-mediamentioning

confidence: 98%

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Allosteric regulation of Arf GTPases and their GEFs at the membrane interface

2016

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“…The involvement of Trp residues in intracellular localization has been reported for a few lipid droplet proteins [32][33][34]. ALDH3B2 contains another Trp residue (Trp469), which is conserved in ALDH3B3, and which is located between Trp462 and the prenylation site ( Figure 5A).…”

Section: The C-terminal Regions Of Aldh3b2 and Aldh3b3 Determine Theimentioning

confidence: 71%

“…Biophysical analysis using NMR demonstrated that the aromaticity of Trp residues results in a tendency for these residues to reside in the electrostatically complex interface environment while the flat rigid shape of the Trp residue limits access to the hydrophobic moiety of the lipid chain [39]. Although the targeting mechanism of proteins to lipid droplets is largely unclear, the importance of Trp residues for lipid droplet localization has been previously reported for proteins including CGI-58, cholesteryl ester transfer protein, and the guanine nucleotide exchange factor GBF1 [32][33][34]. When the C-terminal region of ALDH3B2 was subjected to helical wheel plotting, the Trp462 and Trp469 residues and the prenylated Cys residue (Cys476) were closely oriented ( Figure 6C).…”

Section: Discussionmentioning

confidence: 99%

Mouse aldehyde dehydrogenase ALDH3B2 is localized to lipid droplets via two C-terminal tryptophan residues and lipid modification

Kitamura

Takagi

Naganuma

et al. 2014

Biochemical Journal

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Short title: Lipid droplet localization of ALDH3B2Summary statement: The mouse aldehyde dehydrogenases ALDH3B2 and ALDH3B3 exhibit similar substrate specificity but distinct intracellular localization (ALDH3B2, lipid droplets; ALDH3B3, plasma membrane). The C-terminal prenylation and two Trp residues are important for the lipid droplet localization of ALDH3B2.2 ABSTRACT Aldehyde dehydrogenases (ALDHs) catalyze the conversion of toxic aldehydes to non-toxic carboxylic acids. Of the 21 ALDHs in mice, it is the ALDH3 family members (ALDH3A1, ALDH3A2, ALDH3B1, ALDH3B2, and ALDH3B3) that are responsible for the removal of lipid-derived aldehydes. However, ALDH3B2 and ALDH3B3 have yet to be characterized.Here, we examined the enzyme activity, tissue distribution, and subcellular localization of ALDH3B2 and ALDH3B3. Both were found to exhibit broad substrate preferences from medium-chain to long-chain aldehydes, resembling ALDH3A2 and ALDH3B1. Although ALDH3B2 and ALDH3B3 share extremely high sequence similarity, their localizations differed, with ALDH3B2 found in lipid droplets and ALDH3B3 localized to the plasma membrane. Both ALDH3B2 and ALDH3B3 were modified by prenylation at their C-termini; this modification greatly influenced their membrane localization and enzymatic activity toward hexadecanal. We found that their C-terminal regions, particularly the two Trp residues (Trp462 and Trp469) of ALDH3B2 and the two Arg residues (Arg462 and Arg463) of ALDH3B3, were important for the determination of their specific localization. Abnormal quantity and perhaps quality of lipid droplets are implicated in several metabolic diseases. We speculate that ALDH3B2 acts to remove lipid-derived aldehydes in lipid droplets generated via oxidative stress as a quality control mechanism.

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The perilipin‐2 (adipophilin) coat of cytosolic lipid droplets is regulated by an Arf1‐dependent mechanism in HC11 mouse mammary epithelial cells

Pauloin¹,

Adenot

Hue-Beauvais³

et al. 2015

Cell Biology International

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The cytosolic lipid droplets (cLDs) store excess intracellular lipids, and perilipin-2 is believed to protect cLDs from degradation. Here, we investigated the role of the small G-protein Arf1 and the proteasome in the fates of perilipin-2 and cLDs. In oleate-loaded cells, upon brefeldin A (BFA) treatment, perilipin-2 remained associated with cLDs for at least 30 min before significant release, and proteasomal degradation-mediated decrease was observed. Interestingly, the cLD population did not mimic the decline in perilipin-2. We tested several chemical modulators of regulators of Arf1 activity on the association of perilipin-2 with cLDs. QS11 and Exo2 accelerated the reduction in perilipin-2, although less than BFA. In contrast, Exo1 unexpectedly slowed down its degradation. Correlatively, BFA, QS11, and Exo2 enhanced the dissociation of perilipin-2 from cLDs, whereas Exo1 inhibited it. There was a synergistic effect of BFA with Exo2 and QS11, and of Exo2 with QS11, whereas Exo1 antagonized the effect of BFA without affecting that of Exo2 or QS11. We concluded that the Arf1 complex regulates the association of perilipin-2 with cLDs. Additionally, MG132 and BFA modified the number of cLDs over a relatively short period.

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Targeting of the Arf-GEF GBF1 to lipid droplets and Golgi membranes

Cited by 71 publications

References 45 publications

Allosteric regulation of Arf GTPases and their GEFs at the membrane interface

Allosteric regulation of Arf GTPases and their GEFs at the membrane interface

Mouse aldehyde dehydrogenase ALDH3B2 is localized to lipid droplets via two C-terminal tryptophan residues and lipid modification

The perilipin‐2 (adipophilin) coat of cytosolic lipid droplets is regulated by an Arf1‐dependent mechanism in HC11 mouse mammary epithelial cells

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