HGNC Approved Gene Symbol: GABARAP
Cytogenetic location: 17p13.1 Genomic coordinates (GRCh38) : 17:7,240,008-7,242,449 (from NCBI)
Type-A receptors for the neurotransmitter GABA (gamma-aminobutyric acid) (see 137160) are ligand-gated chloride channels that mediate inhibitory neurotransmission. By performing a yeast 2-hybrid screen on a fetal brain cDNA library using the intracellular loop of the GABA-A receptor gamma-2S subunit (GABRG2; 137164) as bait, followed by screening an adult brain cDNA library, Wang et al. (1999) identified a cDNA encoding GABARAP. Sequence analysis predicted that the 117-amino acid, 13.9-kD GABARAP protein contains a basic N terminus and an acidic C terminus, with an overall pI of 9.6. Northern blot analysis detected a 0.9-kb GABARAP transcript in all tissues tested, namely heart, brain, placenta, lung, liver, skeletal muscle, kidney, and pancreas. Western blot analysis also detected GABARAP expression in all tissues tested, suggesting that GABARAP is also involved in biologic events other than interaction with GABA-A receptors.
Komoike et al. (2010) noted that the GABARAP gene maps to chromosome 17p13.1.
Binding analysis by Wang et al. (1999) showed that the N-terminal 21 amino acids of GABARAP formed an alpha helix that interacted with tubulin (see TUBA1; 191110). Immunoprecipitation and immunohistochemical analysis in rat brain tissues demonstrated association and colocalization of GABARAP and GABA-A receptors.
Apg8 is a ubiquitin-like protein involved in autophagy in yeast. A cysteine protease, Apg4, cleaves Apg8 to create a C-terminal glycine required for ubiquitin-like modification reactions. There are at least 4 mammalian Apg8 homologs: GATE16 (GABARAPL2; 607452), GABARAP, MAP1LC3 (see 601242), and APG8L (GABARAPL1; 607420). Hemelaar et al. (2003) found that mouse Atg4b (611338) acted on the C termini of these 4 Atg8 homologs, and that the reaction required the active-site cysteine of Atg4b. Although the amino acid sequences of these Apg8 homologs differ from one another by as much as 71%, their affinities for Atg4b were roughly comparable in competition experiments.
Using coimmunoprecipitation and mass spectrometric analyses, Lee et al. (2005) identified DDX47 (615428) as a binding partner of GABARAP in human 2774 and SKOV-3 ovarian tumor cell lysates. Yeast 2-hybrid analysis confirmed the interaction. Overexpression of either DDX47 or GABARAP alone had no effect on proliferation of SKOV-3 cells; however, their coexpression inhibited cell proliferation and induced apoptosis.
Behrends et al. (2010) reported a proteomic analysis of the autophagy interaction network (AIN) in human cells under conditions of ongoing (basal) autophagy, revealing a network of 751 interactions among 409 candidate interacting proteins with extensive connectivity among subnetworks. Many new AIN components have roles in vesicle trafficking, protein or lipid phosphorylation, and protein ubiquitination, and affect autophagosome number or flux when depleted by RNA interference. The 6 human orthologs of yeast autophagy-8 (ATG8), MAP1LC3A, MAP1LC3B (609604), MAP1LC3C (609605), GABARAP, GABARAPL1, and GABARAPL2, interact with a cohort of 67 proteins, with extensive binding partner overlap between family members, and frequent involvement of a conserved surface on ATG8 proteins known to interact with LC3-interacting regions in partner proteins. Behrends et al. (2010) concluded that their studies provided a global view of the mammalian autophagy interaction landscape and a resource for mechanistic analysis of this critical protein homeostasis pathway.
Komoike et al. (2010) found that Gabarap was expressed in the telencephalon, hindbrain, and rhombomere of zebrafish during development and later expressed in other brain regions. Knockdown of Gabarap resulted in dwarfism of the entire zebrafish body, as well as a severely hypoplastic head and mandible. The findings suggested that the Gabarap gene plays a role in brain development in zebrafish.
Behrends, C., Sowa, M. E., Gygi, S. P., Harper, J. W. Network organization of the human autophagy system. Nature 466: 68-76, 2010. [PubMed: 20562859] [Full Text: https://doi.org/10.1038/nature09204]
Hemelaar, J., Lelyveld, V. S., Kessler, B. M., Ploegh, H. L. A single protease, Apg4B, is specific for the autophagy-related ubiquitin-like proteins GATE-16, MAP1-LC3, GABARAP, and Apg8L. J. Biol. Chem. 278: 51841-51850, 2003. [PubMed: 14530254] [Full Text: https://doi.org/10.1074/jbc.M308762200]
Komoike, Y., Shimojima, K., Liang, J.-S., Fujii, H., Maegaki, Y., Osawa, M., Fujii, S., Higashinakagawa, T., Yamamoto, T. A functional analysis of GABARAP on 17p13.1 by knockdown zebrafish. J. Hum. Genet. 55: 155-162, 2010. [PubMed: 20111057] [Full Text: https://doi.org/10.1038/jhg.2010.1]
Lee, J. H., Rho, S. B., Chun, T. GABA-A receptor-associated protein (GABARAP) induces apoptosis by interacting with DEAD (Asp-Glu-Ala-Asp/His) box polypeptide 47 (DDX 47). Biotech. Lett. 27: 623-628, 2005. [PubMed: 15977068] [Full Text: https://doi.org/10.1007/s10529-005-3628-2]
Wang, H., Bedford, F. K., Brandon, N. J., Moss, S. J., Olsen, R. W. GABA(A)-receptor-associated protein links GABA(A) receptors and the cytoskeleton. Nature 397: 69-72, 1999. [PubMed: 9892355] [Full Text: https://doi.org/10.1038/16264]