Arl2 (Arf-like 2) GTPases are members of the Arf family that bind GDP and GTP with very low affinity. Unlike most Arf family proteins, Arl2 is not myristoylated at its N-terminal helix. The protein PDE-delta, first identified in photoreceptor rod cells, binds specifically to Arl2 and is structurally very similar to RhoGDI. Despite the high structural similarity between Arl2 and Rho proteins and between PDE-delta and RhoGDI, the interactions between the GTPases and their effectors are very different. In its GTP bound form, Arl2 interacts with the protein Binder of Arl2 (BART), and thecomplex is believed to play a role in mitochondrial adenine nucleotide transport []. In its GDP bound form, Arl2 interacts with tubulin- folding Cofactor D; this interaction is believed to play a role in regulation of microtubule dynamics that impact the cytoskeleton, cell division, and cytokinesis [].This entry also includes Alp41 from fission yeasts which is essential for the cofactor-dependent biogenesis of microtubules [].
This entry represents a group of Arf-like small GTP-binding proteins, including ARL2/3 from animals, Cin4 from budding yeasts, Alp41 from fission yeasts and ARL2 from Arabidopsis. They are involved in microtubule-dependent processes []. Despite the structural similarity of ARL2 and ARL3, they have different biochemical properties and biological functions []. ARL2 plays roles in both the regulation of tubulin folding and microtubule destruction. It is also essential to a number of mitochondrial functions, including mitochondrial morphology, motility, and maintenance of ATP levels []. ARL3 is required for normal cytokinesis and cilia signaling []. Alp41 is essential for the cofactor-dependent biogenesis of microtubules [].
This domain is found in tubulin-binding cofactor C (or tubulin-specific chaperone C) (TBCC) and in protein XRP2. TBCC is a folding cofactor that participates in tubulin biogenesis along with the other tubulin folding cofactors A (TBCA), B (TBCB), E (TBCE) and D (TBCD), as well as the GTP-binding protein Arl2 [, ]. XRP2 is a GTPase-activating protein (GAP) involved in intracellular trafficking [].
This domain superfamily is found in ADP-ribosylation factor-like 2 (ARF2) binding protein, also known as BART. BART binds specifically to ARF2.GTP with a high affinity. However, it does not bind to ARF2.GDP. It is thought that this specific interaction is due to BART being the first identified ARF2-specific effector. The function is not completely characterised []. BART is predominantly cytosolic but can also be found to be associated with mitochondria. BART is also involved in binding to the adenine nucleotide transporter ANT1 [].The interactions between ARL2 and BART involve a conserved N-terminal LLxIL motif of ARL2 []. This domain is also found in CFAP36/CCDC104, a protein renamed as BARTL1. The BART-like domain of CCDC104/BARTL1 recognizes an LLxILxxL motif at the N-terminal amphipathic helix of ARL3 [].
This domain is found in ADP-ribosylation factor-like 2 (ARF2) binding protein, also known as BART. BART binds specifically to ARF2.GTP with a high affinity. However, it does not bind to ARF2.GDP. It is thought that this specific interaction is due to BART being the first identified ARF2-specific effector. The function is not completely characterised []. BART is predominantly cytosolic but can also be found to be associated with mitochondria. BART is also involved in binding to the adenine nucleotide transporter ANT1 [].The interactions between ARL2 and BART involve a conserved N-terminal LLxIL motif of ARL2 []. This domain is also found in CFAP36/CCDC104, a protein renamed as BARTL1. The BART-like domain of CCDC104/BARTL1 recognizes an LLxILxxL motif at the N-terminal amphipathic helix of ARL3 [].
Signal transducers and activators of transcription (STATs) mediate cell proliferation, differentiation and survival in immune responses. ADP-ribosylation factor-like protein 2-binding protein, also known as BART, plays an essential role in the nuclear retention of STAT3 through interaction with GTPase ARL2 (ARF-like 2) []. BART is predominantly cytosolic but can also be found to be associated with mitochondria. BART is also involved in binding to the adenine nucleotide transporter ANT1 and may have a role in mitochondria transport and/or apoptosis [].
Retinal rod rhodopsin-sensitive cGMP 3',5'-cyclic phosphodiesterase () is an oligomer composed of two catalytic chains (alpha and beta), an inhibitory chain (gamma) and a delta chain. This protein interacts with RPGR (retinitis pigmentosa GTPase regulator) [], ARL2 (Arf-like-2) and ARL3. This entry represents the delta subunit [], which is thought to act as a prenyl-binding protein []and participates in the transport of PDE6 catalytic alpha/beta subunits [].
Tubulin proteostasis is regulated by a group of molecular chaperones termed tubulin cofactors (TBC). This entry represents TBCE (tubulin-specific chaperone E), which is an alpha-tubulin binding protein that, together with Arl2 and cofactors D (TBCD), A (TBCA or p14), B (TBCB) and C (TBCC), participate in tubulin biogenesis []. TBCE contains an N-terminal cytoskeleton-associated protein with glycine-rich segment (CAP-Gly) domain, a leucine-rich repeat protein-protein interaction domain followed by leucine-rich repeat (LRR) domains, and a C-terminal ubiquitin-like (Ubl) domain [].Mutations in TBCE gene cause the Kenny-Caffey/Sanjad-Sakati syndrome, characterised by hypoparathyroidism, mental retardation and facial dysmorphism [].
The tubulin heterodimer consists of one alpha- and one beta-tubulin polypeptide. In humans, five tubulin-specific chaperones termed TBCA/B/C/D/E are essential for bring the alpha- and beta-tubulin subunits together into a tightly associated heterodimer. Following the generation of quasi-native beta- and alpha-tubulin polypeptides (via multiple rounds of ATP-dependent interaction with the cytosolic chaperonin), TBCA and TBCB bind to and stabilise newly synthesised beta- and alpha-tubulin, respectively. The exchange of beta-tubulin between TBCA and TBCD, and of alpha-tubulin between TBCB and TBCE, resulting in the formation of TBCD/beta and TBCE/alpha. These two complexes then interact with each other and form a supercomplex (TBCE/alpha/TBCD/beta). Interaction of the supercomplex with TBCC causes the disassembly of the supercomplex and the release of E-site GDP-bound alpha/beta tubulin heterodimer, which becomes polymerization competent following spontaneous exchange with GTP [].This entry represents tubulin-folding cofactor D (TBCD) and its homologues. Its ability to interact with beta tubulin is regulated via its interaction with ARL2 (ADP ribosylation factor-like protein 2), a small monomeric G protein. ARL2 inhibits the beta-tubulin GTPase activating protein (GAP) activity of TBCD, and its interaction with native tubulin dimers [, ].
ELMOD3 (ELMO domain-containing protein 3) is an GTPase-activating protein that acts on Arl2 GTPase. A mutation in the ELMOD3 gene is associated with hearing impairment in humans [].There are six ELMO domain containing proteins identified in humans. They can be classified into two subgroups, ELMOs and ELMODs, according to protein size and domain architecture []. ELMOs are approximately twice as large as ELMODs and contain multiple domains. The function of the ELMO domain is not clear. ELMOs and ELMODs seem to have distinct cellular and biochemical functions. ELMOs interact with DOCKs and enhance the GEF activity of DOCKs, while ELMODs may play a general role in integrating signalling pathways controlled by Arls and other GTPases [, ].
ELMOD2 is an GTPase-activating protein that acts on Arl2 and Arf GTPases [, ]. It has been implicated in idiopathic pulmonary fibrosis (IPF) [, ]. It has also being shown to regulate antiviral responses [].There are six ELMO domain containing proteins identified in humans. They can be classified into two subgroups, ELMOs and ELMODs, according to protein size and domain architecture []. ELMOs are approximately twice as large as ELMODs and contain multiple domains. The function of the ELMO domain is not clear. ELMOs and ELMODs seem to have distinct cellular and biochemical functions. ELMOs interact with DOCKs and enhance the GEF activity of DOCKs, while ELMODs may play a general role in integrating signalling pathways controlled by Arls and other GTPases [, ].
ELMOD1 is an ELMO domain containing protein that activates Arl2 GTPase []and possibly other GTPases of the Arf family []. Mutations in the mouse ELMOD1 gene cause cochlear hair cell dysfunction and hearing loss []. There are six ELMO domain containing proteins identified in humans. They can be classified into two subgroups, ELMOs and ELMODs, according to protein size and domain architecture []. ELMOs are approximately twice as large as ELMODs and contain multiple domains. The function of the ELMO domain is not clear. ELMOs and ELMODs seem to have distinct cellular and biochemical functions. ELMOs interact with DOCKs and enhance the GEF activity of DOCKs, while ELMODs may play a general role in integrating signalling pathways controlled by Arls and other GTPases [, ].
This entry represents the ELMO (EnguLfment and Cell MOtility) domain, which is found in a number of eukaryotic proteins involved in the cytoskeletal rearrangements required for phagocytosis of apoptotic cells and cell motility, including CED-12, ELMO-1 and ELMO-2. ELMO-1 and ELMO-2 are components of signalling pathways that regulate phagocytosis and cell migration and are mammalian orthologues of the Caenorhabditis elegans gene, ced-12 that is required for the engulfment of dying cells and cell migration. ELMO-1/2 act in association with DOCK1 and CRK. ELMO-1/2 interact with the SH3-domain of DOCK1 via an SH3-binding site to enhance the guanine nucleotide exchange factor (GEF) activity of DOCK1. ELMO-1/2 could be part of a complex with DOCK1 and Rac1 that could be required to activate Rac Rho small GTPases. Regulatory GTPases in the Ras superfamily employ a cycle of alternating GTP binding and hydrolysis, controlled by guanine nucleotide exchange factors and GTPase-activating proteins (GAPs), as essential features of their actions in cells. Within the Ras superfamily, the Arf family is composed of 30 members, including 22 Arf-like (Arl) proteins. The ELMO domain has been proposed to be a GAP domain for ARL2 and other members of the Arf family [].
