Structure of the Sec7 domain of the Arf exchange factor ARNO

Cherfils, Jacqueline; Menetrey, J.; Mathieu, Magali; Bras, Gisèle Le; Robineau, Sylviane; Béraud-Dufour, Sophie; Antonny, Bruno; Chardin, Pierre Teilhard de

doi:10.1038/32210

Cited by 176 publications

(144 citation statements)

References 30 publications

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“…Arf1p residue K30 (arf1-105) contacts E97 of ArfGEF, the glutamine finger. Previous biochemical studies have demonstrated that E97 is critical for catalytic activity and that mutation of this residue results in the aberrant formation of a stable but catalytically inert complex between Arf1p and ArfGEF and inhibits nucleotide exchange on Arf1p by wild-type ArfGEF (Béraud-Dufour et al, 1998;Betz et al, 1998;Cherfils et al, 1998;Mossessova et al, 1998). Additional functional data also suggest that interactions between Arf and the FG loop of ArfGEF are indeed important in vivo.…”

Section: Mutations In Proposed Arfgef-binding Site Of Arf1pmentioning

confidence: 60%

Systematic Structure-Function Analysis of the Small GTPase Arf1 in Yeast

Click¹,

Stearns

Botstein³

2002

MBoC

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Members of the ADP-ribosylation factor (Arf) family of small GTPases are implicated in vesicle traffic in the secretory pathway, although their precise function remains unclear. We generated a series of 23 clustered charge-to-alanine mutations in the Arf1 protein ofSaccharomyces cerevisiae to determine the portions of this protein important for its function in cells. These mutants display a number of phenotypes, including conditional lethality at high or low temperature, defects in glycosylation of invertase, dominant lethality, fluoride sensitivity, and synthetic lethality with thearf2 null mutation. All mutations were mapped onto the available crystal structures for Arf1p: Arf1p bound to GDP, to GTP, and complexed with the regulatory proteins ArfGEF and ArfGAP. From this systematic structure-function analysis we demonstrate that all essential mutations studied map to one hemisphere of the protein and provide strong evidence in support of the proposed ArfGEF contact site on Arf1p but minimal evidence in support of the proposed ArfGAP-binding site. In addition, we describe the isolation of a spatially distant intragenic suppressor of a dominant lethal mutation in the guanine nucleotide-binding region of Arf1p.

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Section: Mutations In Proposed Arfgef-binding Site Of Arf1pmentioning

confidence: 60%

Systematic Structure-Function Analysis of the Small GTPase Arf1 in Yeast

Click¹,

Stearns

Botstein³

2002

MBoC

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“…The structure of myristoylated or non-myristoylated Arf1 and [⌬17]Arf1 bound to GDP or GTP and in complex with Sec7 domains revealed the sequential conformational changes and the role of GEFs during nucleotide exchange (21,22,24,28,36,42,46). The protein-protein interface encompasses the Switch 1 and 2 regions (residues 38 -51 and 69 -84, respectively) of Arf1 with the hydrophobic groove and C-terminal helices of the Sec7 domain (Fig.…”

Section: Discussionmentioning

confidence: 99%

“…Sec7 domains form an elongated superhelix of helices with an N-terminal subdomain, carrying the catalytic glutamic residue Glu-156, and a C-terminal subdomain that closes up when associated with Arf1. Well resolved structures of Arf1 bound to GDP and GTP (21)(22)(23), isolated Sec7 domains (24), and free-nucleotide Arf1-Sec7 domain complex are available (25). Moreover, unique to G proteins, transient GDP-bound Arf1-GEF intermediates have been reported using a charge reversal Arno mutant (Glu 156 to Lys) preventing the GDP release (26) or by using the natural inhibitor brefeldin A (BFA) (26).…”

Section: ؉mentioning

confidence: 99%

Kinetics of Interaction between ADP-ribosylation Factor-1 (Arf1) and the Sec7 Domain of Arno Guanine Nucleotide Exchange Factor, Modulation by Allosteric Factors, and the Uncompetitive Inhibitor Brefeldin A

Rouhana

Padilla

Estaran

et al. 2013

Journal of Biological Chemistry

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Background: Kinetic modulations of Arf1-Sec7 domain complex, by the uncompetitive inhibitor brefeldin A and allosteric factors, are not established. Results: Brefeldin A reorients the binary Arf1-Sec7 domain complex to an abortive one with reduced association and dissociation rates. Conclusion: Kinetic hallmarks allow distinguishing the level, nature, and fate of interacting species. Significance: Similar approach will solve the inhibitory mechanism of new inhibitor families of sec7 domains.

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“…Communication between the membrane and the GEF domain involves little direct contact, if any, and can thus be described in the framework of allostery. It is well established that Sec7 domains have little conformational flexibility, 26,27,[29][30][31][32][33] which makes it unlikely that the GEF activity is regulated by conformational changes at the level of the Sec7 domain. In the following sections, we discuss our current knowledge on the regulatory roles of non-catalytic domains of eukaryotic and bacterial ArfGEFs at the membrane interface.…”

Section: The Allosteric Contribution Of Membranes To the Activation Omentioning

confidence: 99%

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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Structure of the Sec7 domain of the Arf exchange factor ARNO

Cited by 176 publications

References 30 publications

Systematic Structure-Function Analysis of the Small GTPase Arf1 in Yeast

Systematic Structure-Function Analysis of the Small GTPase Arf1 in Yeast

Kinetics of Interaction between ADP-ribosylation Factor-1 (Arf1) and the Sec7 Domain of Arno Guanine Nucleotide Exchange Factor, Modulation by Allosteric Factors, and the Uncompetitive Inhibitor Brefeldin A

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

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