LidA, another Rab1-interacting bacterial effector protein [], is translocated by Legionella into the host cytosol at the beginning of infection, and it localized to the Legionella-containing vacuole (LCV) at the cytosolic surface []. It has been shown that tight interaction with Rab1 allows LidA to facilitate the Legionella targeting factor (DrrA/SidM)-catalyzed release of Rab1 from GDP dissociation inhibitors (GDI) []. The base of the protein is formed by two antiparallel coiled-coil structures forming a long coiled-coil domain. This region of LidA interacts with switch and interswitch regions of Rab1 []the nucleotide binding pocket of Rab8a [], hence blocking access to the GDP/GTP-binding site to a great extent [].
Jouberin, also called AHI-1, is expressed in high levels in the brain, gonad tissues, and skeletal muscle. It is an adaptor protein that interacts with the small GTPase Rab8a and regulates it distribution and function, affecting cilium formation and vesicle transport []. Mutations in the AHI-1 gene can cause Joubert syndrome, a disorder characterized by brainstem malformations, cerebellar aplasia/hypoplasia, and retinal dystrophy []. AHI-1 variation is also associated with susceptibility to schizophrenia []and type 2 diabetes mellitus progression []. AHI-1 contains WD40 and SH3 domains. This entry includes the SH3 domain of jouberin.
Proteins in this entry are guanine nucleotide exchange factors (GEF), including RAB3IL1/RAB3IP from animals, Sec2 from budding yeasts and Spo13 from fission yeasts. The mammalian guanine nucleotide exchange factor for Rab-3A (RAB3IL1) may activate RAB3A, a GTPase that regulates synaptic vesicle exocytosis []. The Rab-3A-interacting protein (RAB3IP) may activate RAB8A and RAB8B, which reorganizes actin and microtubules to form new cell surface domains [].In the yeast Saccharomyces cerevisiae, Rab guanine nucleotide exchange factor Sec2 activates Sec4 by catalyzing the dissociation of GDP from Sec4. Activation of Sec4 by Sec2 is needed for the directed transport of vesicles to sites of exocytosis []. In the yeast Schizosaccharomyces pombe, sporulation-specific protein 13 (Spo13) is required for sporulation. During sporulation the spindle pole body (SPB) forms outer plaques, an essential precursor to the assembly of the forespore membrane (FSM). SPB associates with Spo13 and Spo2, and without these genes the SPB is not modified and the FSM does not form [].
MICAL (molecule Interacting with CasL) family is a group of multifunctional proteins that contain the calponin homology (CH), a LIM and a coiled-coil (CC) domains []. They interact with receptors on the target cells, help recruiting other proteins, and promote the modulation of their activity with respect to the downstream events []. There is only one MICAL protein found in Drosophila [], while there are 5 MICAL (MICAL1/2/3, MICAL-like1/2) isoforms found in vertebrates []. Drosophila MICAL and vertebrate MICAL1/2/3 contain an extra N-terminal FAD (flavin adenine dinucleotide binding monooxygenase) domain, whose structure resembles that of a flavo-enzyme, p-hydroxybenzoate hydroxylase []. Drosophila MICAL has an NADPH-dependent actin depolymerising activity []. Vertebrate MICALs are also shown to be effectors of small Rab GTPases, which play important roles in vesicular trafficking []. MICAL-like protein 1 (MICAL-L1) interacts with small G proteins and regulates endocytic recycling of receptors [, ]. It forms a complex with Rab13 that regulates EGFR trafficking at late endocytic pathways []. MICAL-L1 also forms a complex with Arf6 that regulates Rab8a function. MICAL-L1 can be regulated by Rab35 [].MICAL-like protein 2 (MICAL-L2, also known as JRAB) interacts with Rab13 []and Rab8 to regulate the endocytic recycling of occludin, claudin and E-cadherin to the plasma membrane. It may thereby regulate the establishment of tight junctions and adherens junctions []. MICAL-L2/JRAB also regulates the reorganisation of the actin cytoskeleton through interactions with actinin-1, actinin-4, and filamentous actin [], and via filamins during cell spreading [].
MICAL (molecule Interacting with CasL) family is a group of multifunctional proteins that contain the calponin homology (CH), a LIM and a coiled-coil (CC) domains []. They interact with receptors on the target cells, help recruiting other proteins, and promote the modulation of their activity with respect to the downstream events []. There is only one MICAL protein found in Drosophila [], while there are 5 MICAL (MICAL1/2/3, MICAL-like1/2) isoforms found in vertebrates []. Drosophila MICAL and vertebrate MICAL1/2/3 contain an extra N-terminal FAD (flavin adenine dinucleotide binding monooxygenase) domain, whose structure resembles that of a flavo-enzyme, p-hydroxybenzoate hydroxylase []. Drosophila MICAL has an NADPH-dependent actin depolymerising activity []. Vertebrate MICALs are also shown to be effectors of small Rab GTPases, which play important roles in vesicular trafficking []. This entry represents MICAL3. MICAL3 links Rab8A and ELKS (a Rab6-interacting cortical factor). The FAD domain of MICAL3 is required to regulate its own turnover and the associated remodelling of vesicle-docking protein complexes []. Also included in MICAL1 from Danio rerio, which is thought to be an [F-actin]-methionine sulfoxide oxidase.
The entry includes Guanine nucleotide exchange factor C9orf72 protein, a component of the C9orf72-SMCR8 complex, which has guanine nucleotide exchange factor activity []and regulates autophagy [, ]. The C9orf72 protein is proposed to be a catalytic component for the exchange of GDP to GTP and promoting autophagosome maturation by converting inactive GDP-bound RAB8A and RAB39B into their active forms []. Defects in the C9orf72 gene are the cause of frontotemporal dementia and/or amyotrophic lateral sclerosis (FTDALS) which is an autosomal dominant neurodegenerative disorder. The disorder is caused by a large expansion of a GGGGCC hexanucleotide within the first C9orf72 intron located between the first and the second non-coding exons. The expansion leads to the loss of transcription of one of the two transcripts encoding isoform 1 and to the formation of nuclear RNA foci []. This family is found in eukaryotes.C9orf72 contains the DENN domain, which forms a heart-shaped structure (), with the N-terminal residues forming one lobe and the C-terminal residues forming the second one. The tripartite DENN (after differentially expressed in neoplastic versus normal cells) domain is found in several proteins that share common structural features and have been shown to be guanine nucleotide exchange factors (GEFs) for Rab GTPases, which are regulators of practically all membrane trafficking events in eukaryotes [, ].
