This entry includes Ras-related proteins Rab39a and Rab39b. Rab39a is involved in phagosome maturation, inflammatory activation and neuritogenesis [, , ]. It also interacts with PI3K and negatively regulates the LPS-induced autophagy in macrophages []. Rab39b has also been found to be involved in autophagy and neuritogenesis []. Rab39a is widely expressed, while Rab39b is enriched in the brain []. Rabs are regulated by GTPase activating proteins (GAPs), which interact with GTP-bound Rab and accelerate the hydrolysis of GTP to GDP. Guanine nucleotide exchange factors (GEFs) interact with GDP-bound Rabs to promote the formation of the GTP-bound state. Rabs are further regulated by guanine nucleotide dissociation inhibitors (GDIs), which facilitate Rab recycling by masking C-terminal lipid binding and promoting cytosolic localization. Most Rab GTPases contain a lipid modification site at the C terminus, with sequence motifs CC, CXC, or CCX. Lipid binding is essential for membrane attachment, a key feature of most Rab proteins [, ].
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 [, ].
