The domain architecture of large guanine nucleotide exchange factors for the small GTP-binding protein Arf
- Barbara Mouratou†1,
- Valerie Biou†1,
- Alexandra Joubert1,
- Jean Cohen2,
- David J Shields3,
- Niko Geldner4, 5,
- Gerd Jürgens4,
- Paul Melançon3 and
- Jacqueline Cherfils1Email author
© Mouratou et al; licensee BioMed Central Ltd. 2005
Received: 04 November 2004
Accepted: 17 February 2005
Published: 17 February 2005
Small G proteins, which are essential regulators of multiple cellular functions, are activated by guanine nucleotide exchange factors (GEFs) that stimulate the exchange of the tightly bound GDP nucleotide by GTP. The catalytic domain responsible for nucleotide exchange is in general associated with non-catalytic domains that define the spatio-temporal conditions of activation. In the case of small G proteins of the Arf subfamily, which are major regulators of membrane trafficking, GEFs form a heterogeneous family whose only common characteristic is the well-characterized Sec7 catalytic domain. In contrast, the function of non-catalytic domains and how they regulate/cooperate with the catalytic domain is essentially unknown.
Based on Sec7-containing sequences from fully-annotated eukaryotic genomes, including our annotation of these sequences from Paramecium, we have investigated the domain architecture of large ArfGEFs of the BIG and GBF subfamilies, which are involved in Golgi traffic. Multiple sequence alignments combined with the analysis of predicted secondary structures, non-structured regions and splicing patterns, identifies five novel non-catalytic structural domains which are common to both subfamilies, revealing that they share a conserved modular organization. We also report a novel ArfGEF subfamily with a domain organization so far unique to alveolates, which we name TBS (TB C-S ec7).
Our analysis unifies the BIG and GBF subfamilies into a higher order subfamily, which, together with their being the only subfamilies common to all eukaryotes, suggests that they descend from a common ancestor from which species-specific ArfGEFs have subsequently evolved. Our identification of a conserved modular architecture provides a background for future functional investigation of non-catalytic domains.
Guanine Nucleotide Exchange Factors (GEFs) are obligatory components of signaling cascades regulated by small GTP-binding proteins (called small G proteins hereafter). Their biochemical activity is to stimulate the dissociation of the tightly bound GDP nucleotide from the small G protein in response to cellular signals. Thereby, they favor the binding of the more abundant cellular GTP, organizing the active conformation of the small G protein which can recruit its effectors (reviewed in ). Each small G protein family features its own ensemble of GEFs characterized by a conserved catalytic domain responsible for nucleotide exchange, which is generally combined with non-catalytic domains that define the spatio-temporal conditions of activation. In the case of small G proteins of the Arf family, which are major regulators in membrane trafficking (reviewed in ), the exchange domain is a conserved module of ~200 amino acids called the Sec7 domain . Its biochemical (reviewed in ) and structural [5, 6] mechanisms have been investigated in detail. Remarkably, the Sec7 domain is the only domain that is conserved in all ArfGEFs (reviewed in [7, 8]) and it is to some extent interchangeable between species . In contrast, little is known about the functions of the other domains, which are likely to determine intracellular localization of ArfGEFs and their responsiveness to specific signals.
As for most small G proteins, Arf family members are outnumbered by ArfGEFs in many species. In humans for instance, 5 Arf proteins have been identified, and there are at least 13 proteins carrying a Sec7 domain, of which most have been characterized as bona fide ArfGEFs (reviewed in [7, 8]). Thus an individual Arf protein may be activated by more than one GEF, emphasizing that essential aspects in building up the Arf responses may be encoded by the modular architecture of their GEFs. Sequence similarity in the non-catalytic regions forms the basis for the classification of ArfGEFs into subfamilies. 8 subfamilies are currently identified in eukaryotes with sizes ranging from small (~40–80 kD including CYH, EFA6 and FBS), to medium (~100–150 kD, including BRAG/LONER, SYT1, SYT2) and large (~170–200 kD) ArfGEFs (reviewed in [7, 8]). Large ArfGEFs comprise two subfamilies which we will refer to as the BIG and GBF subfamilies after the name of their human representatives. The GBF subfamily includes human GBF1 , Arabidopsis GNOM  and Saccharomyces Gea1 and Gea2 , the BIG subfamily human BIG1 and BIG2 [13, 14] and yeast Sec7p . An additional subfamily called RalF is found in Rickettsie and Legionella bacteria, likely acting on an host Arf pathway . Analysis of the CYH and EFA6 subfamilies, present only in multicellular animals, and that of the large ArfGEFs, found in all eukaryotes, have yielded most of the functional data currently available. CYH and EFA6 are active on Arf6 at the plasma membrane where they may function in the crosstalk of membrane traffic, cytoskeleton dynamics and signalling in endosomal pathways (reviewed in ). Most members of the BIG and GBF subfamilies characterized so far function in vesicular trafficking at the Golgi [12, 14, 18], except for BIG2, which also localizes on recycling endosomes , and GNOM which acts in the endosomal recycling pathway .
The domain architecture of non-catalytic regions of ArfGEFs, hence their contribution to specific aspects of the build-up of the Arf response, is essentially not established except for those ArfGEFs with domains found in other classes of cellular regulators. The known domains include membrane-interacting PH domains in the CYH (reviewed in ), EFA6  and possibly BRAG/LONER subfamilies, and a putative F-box in the FBS subfamily , a protein-protein interaction domain that has been involved in the recruitment of substrates to the SCF ubiquitination machinery. Coiled-coil structures have also been predicted in the N-terminus of the CYH subfamily and in the C-terminus of the EFA6 subfamily. In CYH, they are involved in dimerization , recruitment of partners  and Golgi targeting , and in actin remodeling functions in the case of EFA6 . On the other hand, although the functions of BIG and GBF subfamilies have been the subject of many investigations, their architecture is barely described, making it difficult to associate biochemical activities with their molecular structure.
Here we investigate the domain architecture in the BIG and GBF subfamilies, including all sequences from fully annotated eukaryotic genomes and our novel annotation of Sec7-containing proteins from the Paramecium tetraurelia alveolate. Sequence comparisons combined with secondary structures and splicing patterns analysis identifies five novel domains that are conserved between BIG and GBF subfamilies, thus unifying them as a higher order subfamily with a probable common ancestor. Our analysis of Sec7-domain containing sequences from Paramecium also introduces a novel subfamily of ArfGEFs unique to alveolates, which we call TBS (TB C-S ec7).
Results and discussion
A conserved domain architecture in BIG and GBF subfamilies
BIG and GBF protein sequences used in this study.
Protein name a
Size in amino acids
Alternate splice variants of human GBF1, BIG1 and BIG2 a,b
Change in protein
Apparent cause of variation in transcript
Extra Q at 337, 55 residues upstream of HUS domain
Insertion of 3 nucleotides (nt) resulting from use of alternate 3' acceptor site within intron during splicing of exons 10 and 11
New Ser and loss of 14 residues at 613, between HUS and Sec7 domains
Loss of 36 nt resulting from use of alternate 5' donor site within exon 15 during splicing with exon 16
Loss of VSQD at 1494, 38 residues upstream of HDS3
Loss of 12 nt resulting from use of alternate 5' donor site within exon 33 during splicing with exon 34
Frame-shift at 1625 causing loss of last 19 residues of HDS3
Intron retention between exons 36 and 37 leading to frame shift and premature termination
Loss of 38 residues starting at 1784, near C-terminus
Loss of 114 nt resulting from use of novel cryptic splice donor and acceptor sites within exon 40.
Frame-shift at 1340, 32 residues upstream of HDS3
Loss of 59 nt resulting from use of alternate 5' donor site within exon 28 during splicing with exon 29
Loss of VSEKPL at 1557, 68 residues downstream of HDS3
Loss of 18 nt resulting from use of alternate 5' donor site within exon 33 during splicing to exon 34
New T and loss of 33 residues at 1607, 118 residues downstream of HDS3
Loss of 96 nt resulting from use of alternate 3' acceptor site within exon 35 during splicing with exon 34
Frame-shift at 1542, 106 residues downstream of HDS3
Loss of exon 35 resulting from splicing of 5'donor site of exon 34 with 3' acceptor site of exon 36
Evolution of BIGs and GFBs from a common ancestor
The tree topology strongly suggests that in most organisms, GBG members sort in separate branches, corresponding to their classification in BIGs and GBFs. Remarkably, our annotation of Sec7-containing proteins in the genome of Paramecium reveals the first departure from this distribution, as all GBGs in this species are located in a single branch, which is closer to the BIGs. This unexpected tree topology may indicate that alveolates diverged from animals/fungi and plants before the duplication of an ancestral GBG into the BIG and GBF, and that GBGs in that organism are representative of this ancestral gene. Alternatively, duplication may have been followed by loss of GBF genes. Current knowledge of the phylogenetic branching of alveolates relative to the plants and animal/fungi branches does not permit resolution between those two possibilities.
GBGs in plants: refining the functional evolution of BIGs and GBFs
In fungi and mammals, BIGs and GBFs are represented by only one or two members, whose functions in vesicular trafficking at the Golgi within each group appear largely overlapping [12, 14]. In contrast, plants encode a large number of GBGs in both the BIG and GBF branches but lack other ArfGEFs (Figures 1, 8). In Arabidopsis, none of the GBGs map to duplicated chromosomes where identical functions may be encoded [26, 29]. In addition, comparative analysis with the rice genome nearing completion identifies at least five branches each represented by one rice and one or two Arabidopsis homologs (Figure 8). This correspondence between two highly divergent plant species indicates that GBGs diversified early during plant evolution, probably reflecting functional specialization along with the establishment of plant multicellularity. While GNOM has a plant-specific function in recycling plasma-membrane proteins needed for cell-cell communication and cell polarity establishment , possibly closer to the function of EFA6 or CYH subfamilies in metazoans, other plant GBGs are expected to fulfill the presumed ancient function of regulating Golgi trafficking exemplified by mammalian and yeast GBGs. Comparison of orthologous pairs in plants further reveals that they have different sensitivities to Brefeldin A (a widely used fungal inhibitor of Golgi traffic) as predicted from the sequences of the binding site of the drug carried by the Sec7 domain . This observation clearly illustrates that differences in outcome following BrefeldinA treatment may not reflect differences in underlying molecular mechanisms, but instead simply reflect neutral sequence differences at the Sec7 domains between species. In particular, not all BIGs may be BFA-sensitive or GBFs BFA-resistant, unlike suggested by their original nomenclature.
A novel ArfGEF subfamily in alveolates
A conserved scenario for the activation of Arf proteins by their GEFs?
The identification of a conserved modular architecture in all GBG subfamily members suggests that the mechanistic basis for their activation of Arf is likely to follow a similar scenario. Candidate functions for the conserved domains include oligomerization, the collection of input signals, membrane localization, regulation of the exchange activity, scaffolding of Arf proteins to their downstream effectors, not excluding signaling to partners outside the Arf pathways. Dimerization has been reported in the BIG subgroup for BIG1, which forms heterodimers with the highly homologous BIG2 ArfGEF , and in the GBF subgroup for GNOM, which forms homodimers . The conservation of the DCB domain in GBGs, which is responsible for the dimerization of GNOM, suggests that such a dimerization function may be general to this domain in GBGs. Another unresolved issue is the conservation of the cellular partners effecting the functions associated with the conserved domains. Our identification of an almost invariant motif in the HUS domain argues in favor of this domain interacting with a conserved partner. However, the ancient divergence into the BIG and GBF groups and their subsequent divergence into species-specific members suggest that specialized requirements are likely to have evolved in most organisms, possibly yielding less conserved partners outside the Sec7 and HUS domains. Finally, whereas in plants all ArfGEFs are predicted to function according to the scheme defined by the conserved domains, other species have additional ArfGEF subfamilies with a modular architecture unrelated to that of the GBG subfamily. It is not known to what extent the GBG's scenario for Arf activation will also apply to non-GBGs ArfGEFs, acting alone or in association with protein partners. In the case of the GBGs, our definition of the structural homology domains as reported here should now provide a robust background for future investigations of their interactions and functions.
Protein sequence databases were searched with amino acid sequences from human BIG1, human GBF1 and Arabidopsis GNOM using the BLAST algorithm . Paramecium tetraurelia genes were identified with the BLAST algorithm using genome sequence data from Genoscope  and manually annotated using Artemis . Tetrahymena sequences were retrieved from the Tetrahymena thermophila genome sequencing project server . Arabidopsis sequences were retrieved from the Arabidopsis Genome Initiative database , rice sequences from the TIGR Rice annotation project . Splice variants for hGBF1, hBIG1 and hBIG2 were identified from information provided under Aceview in the December (03) release for their respective listings at the NCBI . Multiple sequence alignments were performed using ClustalW  with default alignment parameters or T-coffee [40, 41]. Reliability of the alignments was evaluated according to the T-coffee score, and ranged from average to good for all predicted domains. Average sequence identities were respectively 24 % (DCB domain), 26 % (HUS domain), 44% (Sec7 domain), 26% (HDS1 domain), 28% (HDS2 domain) and 21% (HDS3 domain). Aligned sequences were displayed with ESPript  using a similarity global score of 0.15 calculated using the BLOSUM62 matrix. Unrooted phylogenetic trees were generated using the neighbor-joining algorithm of ClustalW excluding gapped regions, and with a maximum likelihood method using the PHYML package . Phylogenetic trees for individual domains was performed on the subset of sequences used in Figure 3. The reliability of the trees was assessed by a bootstrap analysis (1000 replicates). Trees were drawn with TreeView version 1.6.6. Secondary structure predictions on aligned sequences were carried out with the PHD program along with the ClustalW multiple alignment . Non-structured linkers poor in hydrophobic residues were predicted with the PONDR algorithm .
Guanine nucleotide exchange factor. CYH: cytohesins/ARNO
Exchange Factor for Arf6
Golgi-associated BFA-resistant guanine nucleotide exchange Factor
BFA-Inhibited Guanine nucleotide exchange factor
S uppressor of ypt. DCB: Dimerization/Cyclophilin Binding
Homology Upstream of Sec7
Homology Downstream of Sec7
This work was supported by a Human Frontiers in Science Program grant to G.J., P.M. and J.Ch. We thank Genoscope for access to Paramecium whole genome shotgun primary data and Linda Sperling (CNRS, Gif-sur-Yvette) for help with annotations.
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