ARF-Like (ARL) Proteins - Ras Superfamily Small G Proteins: Biology and Mechanisms 2 - page 222

S. cerevisiae the ARF GAP Gcs1p is also active as an ARL1 GAP (Liu et al. 2005 ).
Although the evidence that Gcs1p is a bona fide ARL1 GAP is convincing
(Liu et al. 2005 ), there is currently no evidence that this activity is conserved in
the human ortholog of Gcs1, ARFGAP1. It is also difficult to differentiate the
function(s) of Gcs1p as an ARL1 or ARF GAP, given the spatial and functional
overlap in the GTPase substrates. We focus here primarily on the mammalian ARL
GAPs. ELMODs have been implicated in deafness, idiopathic pulmonary fibrosis
(IPF), and a diverse array of cellular functions. Cofactor C is involved primarily in
tubulin polymerization. RP2 facilitates traffic of proteins to the cilium and is
mutated in the most severe form of retinitis pigmentosa. Each of these activities
and links to disease are discussed in detail below. Because these five known GAPs
have been studied most extensively or were first discovered as ARL2/ARL3 GAPs
we have positioned this section between these two GTPases. As described below,
the specificities of these GAPs are incompletely characterized, but such data are
likely to reveal more specific roles in multiple signaling pathways.
ELMODs are ancient proteins with promiscuous specificity for ARF family
GTPases (East et al. 2012 ; Ivanova et al. 2014 ). The three ELMODs make up
one-half of the ELMO family of proteins in humans, named for the functions of
ELMO1 and ELMO2 in regulating e ngu l fment and cell mo tility. The only region of
homology shared by ELMODs and ELMOs is within a single domain termed the
ELMO domain and there is currently no evidence that ELMO1-3 possess GAP
activity for any ARF family GTPase. Phylogenetic analysis of the ELMO family of
proteins confirmed that ELMODs and ELMOs represent two phylogenetically
distinct groups of proteins (East et al. 2012 ). ELMODs were found in a wide
sampling of eukaryotes and were likely present in the last eukaryotic common
ancestor, suggesting some function of the ELMODs that is certainly ancient and
likely essential. In contrast, the ELMOs arose later in evolution, contain within
them additional domains, and lack the conserved, putative catalytic arginine
required for GAP activity (East et al. 2012 ). ELMOD1 and ELMOD2 were the
first mammalian ARL GAPs to be reported and exhibited GAP activity against
ARL2 (Bowzard et al. 2007 ). Though initially reported to lack ARL2 GAP activity,
we later found that ELMOD3 does have such activity, but its specific activity is
very low, compared to its paralogs ELMOD1 and ELMOD2 (Ivanova et al. 2014 ).
ELMOD1-3 possess highly variable levels of GAP activity against ARL1, ARL2,
ARL3, ARF1, and ARF6 but are inactive as GAPs for ARL13B (Jaworek
et al. 2013 ; Ivanova et al. 2014 ). These results are intriguing because ELMODs
lack the canonical ARF GAP domain present in every other known ARF GAP that
includes a four cysteine zinc finger and conserved, catalytic arginine (Schlacht
et al. 2013 ). The GAP domain of ELMODs lies within the ELMO domain and a
highly conserved arginine residue was found to be essential for efficient GAP
activity for both ARL2 and ARF1, suggesting a single, novel GAP domain (East
et al. 2012 ). Thus, ELMODs and Gcs1p represent the first evidence for cross talk
between ARFs and ARLs at the level of GAPs. Each of the three ELMODs also
binds the non-opioid sigma-1 receptor (SigmaR1). When co-expressed and purified
as a complex with GST-ELMOD1 or GST-ELMOD2, SigmaR1 almost completely