ARF-Like (ARL) Proteins - Ras Superfamily Small G Proteins: Biology and Mechanisms 2 - page 213

register along the length of the protein to connect the N-terminal helix to the
guanine nucleotide binding site. However, a number of ARLs have very divergent
guanine nucleotide-binding properties (e.g., ARL2 (Hanzal-Bayer et al. 2005 ) and
ARL13B (Miertzschke et al. 2013 ), which suggests that caution is warranted before
assuming too much about whether the conservation of some of these canonical
properties of ARFs hold true among the ARLs. Thus, one of the challenges ahead is
to decipher the extent to which the models emerging for ARFs will hold true for the
entire family and which ARLs have evolved distinctive actions and mechanisms for
achieving their own cell functions.
A few common themes are important to be kept in mind in order to understand
the actions of the ARF family. (1) Effectors lack a defined ARF- or ARL-binding
domain and thus no common structural domain has been conserved that allows one
to search protein databases for predicted binding partners or effectors. Perhaps the
closest thing we have is the GRIP domain, some of which bind ARL1-GTP (Munro
and Nichols 1999 a; Jackson 2003 ; Lu and Hong 2003 ; Panic et al. 2003 ; Derby
et al. 2004 ; Lu et al. 2004 ; Wu et al. 2004 ; Short et al. 2005 ). (2) Effectors bind
specific ARFs and ARLs in a GTP-dependent manner but often with relatively low
affinity and a dependence on lipids/detergents, making many commonly used
co-purification strategies inefficient. (3) This is not to suggest that high-affinity
interactions are not involved; rather simply to point out that effectors of ARFs or
ARLs lack a common domain. (4) Each GTPase in the family appears to bind and
regulate more than one downstream effector, making the regulation of localization
and sources of specificity key questions to address in assessing biological roles of
each family member. (5) To date, each ARL is found to localize and act in more
than a single cellular location. This emphasizes the central issue of the means of
localization, but we also believe this commonly provides essential cross talk
between organelles. (6) Finally, the shared or distinctive specificities of ARF family
members with regulators, notably the guanine nucleotide activating proteins
(GAPs) and guanine nucleotide exchange factors (GEFs), are critical determinants
of the temporal and spatial regulation of the signals generated, and also provide
cross talk between pathways.

10.2 ARL1

ARL1 is the most ARF-like of the ARLs and arguably should have been named
ARF7, based upon similarities in localization and apparent cellular actions.
ADP-ribosylation factor-like 1 (ARL1) was discovered in a genomic study of
Drosophila melanogaster , where it was found to be an essential gene for develop-
ment (Tamkun et al. 1991 ) and later shown also to be essential for viability in
trypanosomes (Price et al. 2005 ). The mammalian isoform that was later identified
(Schurmann et al. 1994 ) shares 57 % sequence identity with human ARF1, more
than any other ARL. Typical of the ARF family, ARL1 contains an amphipathic,
N-terminal

α -helix, which is myristoylated (Lee et al. 1997 ), and is required for