Arf Proteins and Their Regulators: At the Interface Between Membrane Lipids and the Protein Trafficking Machinery - Ras Superfamily Small G Proteins: Biology and Mechanisms 2 - page 153

Fig. 8.2 The domain structure of the major cellular families of Arf GEFs. The domains of the five
major families of Arf GEFs are shown, approximately to scale. Representative members shown are
from humans and budding yeast. The well-characterized Arf substrates for each family are listed,
and the sensitivity (Sens) or resistance (Resist) of their exchange activity to brefeldin A is
indicated. DCB dimerization and cyclophilin binding, HUS homology upstream of Sec7, HDS
homology downstream of Sec7, CC coiled coil, PH pleckstrin homology, E6H EFA6 homology,
IQ isoleucine-glutamine motif
recently a form of bilateral cleft lip has been associated with a deletion of a
chromosomal region including the FBXO8 gene (Calcia et al. 2013 ). RalF is the
founding member of a family of bacterial Arf1 GEFs, first identified in Legionella
pneumophila and Rickettsia prowazekii (Amor et al. 2005 ; Cox et al. 2004 ). These
GEFs do not have a prokaryotic origin, but rather were incorporated into bacterial
genomes through horizontal transfer from their eukaryotic hosts (Nagai et al. 2002 ).
The Sec7 domain of RalF is autoinhibited by the capping domain of the protein,
which is relieved by interaction with a specific lipid environment (Alix et al. 2012 ;
Folly-Klan et al. 2013 ).
There are 11 subfamilies of Arf GAPs, 10 of which are found in humans
(Schlacht et al. 2013 ) (Table 8.3 ). A recent phylogenetic study has indicated that
six Arf GAP families (ArfGAP1, ArfGAP2/3, SMAP, ACAP, AGFG, and the
newly identified ArfGAPC2 family) are ancient, probably existing in the LECA
prior to separation of the eukaryotic supergroups. On the other hand, ASAP, ARAP,
and GIT families arose more recently in evolution, being found only in animals.
Through the course of evolution, the Arf GAPs have undergone extensive domain
shuffling, losing and gaining different domains in a complex pattern to give rise to
the proteins existing today (Schlacht et al. 2013 ). The PH, BAR, RhoGAP, ankyrin
repeat, and C2 domains of Arf GAP proteins are conserved across eukaryotes, and
therefore were probably present in the primordial Arf GAPs, whereas other
domains such as GOLD, CALM, and SH3 domains are restricted to specific
lineages (Schlacht et al. 2013 ).
The first Arf GAP identified was ArfGAP1 (Cukierman et al. 1995 ), which has
two ALPS motifs in its C-terminal region that mediate specific binding to the highly