GABARAP

Summary

GABARAP (GABA type A receptor-associated protein, HGNC:4067) is a protein-coding gene on chromosome 17p13.1, encoding Gamma-aminobutyric acid receptor-associated protein (O95166). Ubiquitin-like modifier that plays a role in intracellular transport of GABA(A) receptors and its interaction with the cytoskeleton.

Gamma-aminobutyric acid A receptors [GABA(A) receptors] are ligand-gated chloride channels that mediate inhibitory neurotransmission. This gene encodes GABA(A) receptor-associated protein, which is highly positively charged in its N-terminus and shares sequence similarity with light chain-3 of microtubule-associated proteins 1A and 1B. This protein clusters neurotransmitter receptors by mediating interaction with the cytoskeleton.

Source: NCBI Gene 11337 — RefSeq curated summary.

At a glance

• GWAS associations: 1
• Clinical variants (ClinVar): 7 total
• Druggable target: yes
• MANE Select transcript: NM_007278

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:4067
Approved symbol	GABARAP
Name	GABA type A receptor-associated protein
Location	17p13.1
Locus type	gene with protein product
Status	Approved
Aliases	MM46, ATG8A
Ensembl gene	ENSG00000170296
Ensembl biotype	protein_coding
OMIM	605125
Entrez	11337

Gene structure

Transcript identifiers

Ensembl transcripts: 7 — 6 protein_coding, 1 nonsense_mediated_decay

ENST00000302386, ENST00000570856, ENST00000571129, ENST00000571253, ENST00000573928, ENST00000577035, ENST00000914967

RefSeq mRNA: 1 — MANE Select: NM_007278 NM_007278

CCDS: CCDS11092

Canonical transcript exons

ENST00000302386 — 4 exons

Exon	Start	End
ENSE00001293387	7240008	7240919
ENSE00002670447	7242241	7242449
ENSE00003489672	7241342	7241460
ENSE00003640094	7241601	7241679

Expression profiles

Bgee: expression breadth ubiquitous, 147 present calls, max score 99.81.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 335.6583 / max 2181.6478, expressed in 1828 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
164169	313.2947	1828
164168	20.1975	1718
164165	1.2697	685
164166	0.5951	320
164167	0.3013	137

Top tissues by expression

147 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
left testis	UBERON:0004533	99.81	gold quality
right testis	UBERON:0004534	99.81	gold quality
pituitary gland	UBERON:0000007	99.74	gold quality
adenohypophysis	UBERON:0002196	99.74	gold quality
monocyte	CL:0000576	99.70	gold quality
leukocyte	CL:0000738	99.69	gold quality
blood	UBERON:0000178	99.69	gold quality
right adrenal gland	UBERON:0001233	99.69	gold quality
right adrenal gland cortex	UBERON:0035827	99.69	gold quality
granulocyte	CL:0000094	99.66	gold quality
prefrontal cortex	UBERON:0000451	99.66	gold quality
left adrenal gland	UBERON:0001234	99.66	gold quality
spinal cord	UBERON:0002240	99.66	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	99.66	gold quality
left adrenal gland cortex	UBERON:0035825	99.66	gold quality
hypothalamus	UBERON:0001898	99.65	gold quality
substantia nigra	UBERON:0002038	99.64	gold quality
frontal cortex	UBERON:0001870	99.62	gold quality
frontal lobe	UBERON:0016525	99.62	gold quality
endocervix	UBERON:0000458	99.61	gold quality
right lobe of thyroid gland	UBERON:0001119	99.61	gold quality
right lung	UBERON:0002167	99.61	gold quality
ganglionic eminence	UBERON:0004023	99.61	gold quality
embryo	UBERON:0000922	99.60	gold quality
putamen	UBERON:0001874	99.60	gold quality
adrenal gland	UBERON:0002369	99.60	gold quality
anterior cingulate cortex	UBERON:0009835	99.60	gold quality
Brodmann (1909) area 9	UBERON:0013540	99.60	gold quality
cerebral cortex	UBERON:0000956	99.59	gold quality
left lobe of thyroid gland	UBERON:0001120	99.59	gold quality

Single-cell (SCXA)

Detected in 25 experiment(s), a significant marker in 19.

Experiment	Marker?	Max mean expression
E-HCAD-6	yes	661.44
E-HCAD-4	yes	342.75
E-HCAD-1	yes	106.84
E-CURD-122	yes	84.21
E-MTAB-6701	yes	79.36
E-MTAB-8410	yes	58.99
E-MTAB-10553	yes	46.67
E-MTAB-9467	yes	42.69
E-CURD-46	yes	40.52
E-HCAD-9	yes	28.74
E-MTAB-9221	yes	27.79
E-MTAB-6678	yes	24.78
E-CURD-88	yes	24.05
E-CURD-112	yes	21.79
E-GEOD-135922	yes	19.59

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): CREB1

miRNA regulators (miRDB)

48 targeting GABARAP, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-4725-3P	99.96	69.53	2520
HSA-MIR-6780B-5P	99.96	69.60	2562
HSA-MIR-4267	99.96	66.53	2368
HSA-MIR-6721-5P	99.93	68.92	2981
HSA-MIR-4731-5P	99.89	67.23	2537
HSA-MIR-4271	99.88	68.32	2244
HSA-MIR-765	99.84	68.24	2442
HSA-MIR-6739-5P	99.80	67.87	2806
HSA-MIR-11181-3P	99.75	66.38	2205
HSA-MIR-6733-5P	99.74	67.94	2759
HSA-MIR-4428	99.73	66.41	1733
HSA-MIR-4306	99.72	70.50	3630
HSA-MIR-3059-5P	99.70	69.93	2491
HSA-MIR-3202	99.66	67.70	2737
HSA-MIR-6887-3P	99.66	67.83	1778
HSA-MIR-6073	99.60	70.36	793
HSA-MIR-3140-5P	99.39	69.04	1136
HSA-MIR-185-5P	99.35	68.60	2497
HSA-MIR-4644	99.35	69.12	2514
HSA-MIR-542-3P	99.34	67.58	1270
HSA-MIR-4667-3P	99.26	65.45	1608
HSA-MIR-449B-3P	99.20	67.24	1047
HSA-MIR-4504	99.10	69.14	1328
HSA-MIR-877-3P	99.09	68.10	1637
HSA-MIR-3619-5P	99.00	68.87	2308
HSA-MIR-4764-5P	98.88	65.53	894
HSA-MIR-214-3P	98.71	68.12	2128
HSA-MIR-761	98.71	68.07	2051
HSA-MIR-1199-5P	98.44	66.51	829
HSA-MIR-6751-3P	98.44	66.35	835

Literature-anchored findings (GeneRIF, showing 40)

• Sequence-specific 1H, 13C and 15N resonance assignments of human GABA receptor associated protein. (PMID:11727985)
• Backbone 1H, 13C, and 15N resonance assignments for a 14 kD protein, GABA(A) receptor associated protein (GABARAP). (PMID:11727986)
• We present the three-dimensional structure of GABARAP obtained by x-ray diffraction at 1.75 A resolution (PMID:11729197)
• Human Apg3p/Aut1p homologue is an authentic E2 enzyme for multiple substrates, GATE-16, GABARAP, and MAP-LC3, and facilitates the conjugation of hApg12p to hApg5p (PMID:11825910)
• Solution structure of human GABA(A) receptor-associated protein GABARAP: implications for biolgoical funcrion and its regulation (PMID:11875056)
• Gec1/GABARAPL1 was more expressed than GABARAP in the central nervous system (CNS), while GABARAP was more expressed in endocrine glands. (PMID:14625090)
• GABARAP mRNA expression and protein expression were significantly down-regulated in invasive ductal and invasive lobular carcinomas; GABARAP acts via a vesicle transport mechanism as a tumor suppressor in breast cancer. (PMID:15695379)
• GABARAP and DDX 47 are involved in the apoptotic process (PMID:15977068)
• Phosphatidylserine and phosphatidylethanolamine are targets of the mammalian Atg8 modifiers, LC3, GABARAP, and GATE-16 (PMID:16303767)
• GABARAP does not alter receptor kinetics directly, but by facilitating surface expression of alphabetagamma receptors. (PMID:16339017)
• Results suggest that lysosomal turnover of GABARAP-PL is activated during the differentiation of C2C12 cells to myotubes without inactivation of the mTor kinase-signaling pathway. (PMID:16874098)
• GABARAP and DLG4 genes are involved in the etiology of nicotine dependence in European-American smokers. (PMID:17164261)
• The association of structurally altered GABARAP protein together with GABA(A) receptor downstream of Ca2+/calmodulin-dependent protein kinase II (CAMKII) activation is essential for long-term potentiation. (PMID:17581966)
• The X-ray structure of the soluble form of human GABA(A) receptor-associated protein complexed with a high-affinity synthetic peptide at 1.3 A resolution, is presented. (PMID:18638487)
• Molecular modeling of a complex containing full-length calreticulin suggests a novel mode of substrate interaction, which may have functional implications for the calreticulin/calnexin family in general. (PMID:19154346)
• The proapoptotic protein Nix/Bnip3L was found to be a potential GABARAP ligand. (PMID:19363302)
• analysis of human NSF possible binding mode to GABARAP and GATE-16 (PMID:19533740)
• DLG4/PSD95 and GABARAP were analyzed using zebrafish embryos with morpholino knockdown system as a model organism. (PMID:20111057)
• Used diffusion-ordered nuclear magnetic resonance spectroscopy to study the temperature and concentration dependence of the diffusion properties of GABARAP. (PMID:20665069)
• Evidence suggests that changes in the expression and function of GABA(A) receptors are involved in the pathogenesis of epilepsy (review) (PMID:21376781)
• The level of GABARAPs is decreased in Lewy body disease. (PMID:21684337)
• Taken together, our results indicate that GABARBP can regulate the pro-apoptotic activity of cisplatin via the upregulation of p53 expression. (PMID:23545901)
• These results support the regulatory role of Bcl-2 in autophagy and define GABARAP as a novel interaction partner involved in this intricate connection. (PMID:24240096)
• knockdown of LC3B but not GABARAPs resulted in significant accumulation of p62/Sqstm1, one of the selective substrates for autophagy (PMID:24582747)
• GABARBP dramatically inhibited VEGF-induced endothelial cell proliferation, migration, and tube formation, as well as VEGFR-2 phosphorylation in vitro. (PMID:24686084)
• The FLCN-GABARAP association is modulated by the presence of either folliculin-interacting protein (FNIP)-1 or FNIP2 and further regulated by ULK1. (PMID:25126726)
• A functional complementation of an lgg-1 null mutant with human GABARAP, its closer homolog showed that it localizes to autophagosomes and can rescue LGG-1 functions in the early embryo. (PMID:25126728)
• The interaction of GABARAP with Mulan-Ube2E3 supports the role of Mulan as an important regulator of mitophagy. (PMID:25224329)
• PLEKHM1 regulates autophagosome-lysosome fusion through homotypic fusion and protein sorting complex and LC3/GABARAP proteins. (PMID:25498145)
• KBTBD6 and KBTBD7 specifically bind to GABARAP proteins.GABARAP proteins mediate localized ubiquitylation of TIAM1 by CUL3. (PMID:25684205)
• Data show that WAC directly binds to GM130 and that this binding is required for autophagosome formation through interacting with GABARAP regulating its subcellular localization. (PMID:26687599)
• GABRP plays an important role in placentation and this pathway may be a promising molecular target for the development of novel therapeutic strategies for preeclampsia. (PMID:27221053)
• Cardiolipin interaction with various Atg8 human orthologs, namely LC3B, GABARAPL2 and GABARAP, was investigated. (PMID:27764541)
• Although neither GABARAPs nor LC3s are required for autophagosome biogenesis, loss of all Atg8s yields smaller autophagosomes and a slowed initial rate of autophagosome formation. (PMID:27864321)
• Development of LC3/GABARAP sensors containing a LIR and a hydrophobic domain to monitor autophagy. (PMID:28320742)
• GABAergic synapse is proposed as a focus of aging. (Review) (PMID:28497576)
• GABARAPs are identified as the first known direct interaction partners of Nef that are essential for its plasma membrane localization. (PMID:28729737)
• The centrosome and centriolar satellites regulate autophagosome formation by delivery of an ATG8-family member, GABARAP, to the forming autophagosome membrane, the phagophore. Its proposed that GABARAP regulates phagophore expansion by activating the ULK complex. [review] (PMID:28990689)
• We have also observed membrane aggregation induced by ATG3 in vitro, which could point to a more complex function of this protein in AP biogenesis. Moreover, in vitro GABARAP lipidation assays suggest that ATG3-membrane interaction could facilitate the lipidation of ATG8 homologues. (PMID:29142222)
• These results indicate that GABARAP and PI4K2A interact tightly. Although lipidation of GABARAP is essential for its role in autophagy, here we show that its lipidation is not required for the interaction of GABARAP and PI4K2A. (PMID:29792687)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
mus_musculus	Gabarap	ENSMUSG00000018567
rattus_norvegicus		ENSRNOG00000062718
drosophila_melanogaster	Atg8b	FBGN0038539
caenorhabditis_elegans		WBGENE00002980

Paralogs (6): GABARAPL2 (ENSG00000034713), MAP1LC3A (ENSG00000101460), GABARAPL1 (ENSG00000139112), MAP1LC3B (ENSG00000140941), MAP1LC3C (ENSG00000197769), MAP1LC3B2 (ENSG00000258102)

Protein

Protein identifiers

Gamma-aminobutyric acid receptor-associated protein — O95166 (reviewed: O95166)

Alternative names: GABA(A) receptor-associated protein, MM46

All UniProt accessions (5): O95166, H6UMI1, I3L236, I3L3J4, Q6IAW1

UniProt curated annotations — full annotation on UniProt →

Function. Ubiquitin-like modifier that plays a role in intracellular transport of GABA(A) receptors and its interaction with the cytoskeleton. Involved in autophagy: while LC3s are involved in elongation of the phagophore membrane, the GABARAP/GATE-16 subfamily is essential for a later stage in autophagosome maturation. Through its interaction with the reticulophagy receptor TEX264, participates in the remodeling of subdomains of the endoplasmic reticulum into autophagosomes upon nutrient stress, which then fuse with lysosomes for endoplasmic reticulum turnover. Also required for the local activation of the CUL3(KBTBD6/7) E3 ubiquitin ligase complex, regulating ubiquitination and degradation of TIAM1, a guanyl-nucleotide exchange factor (GEF) that activates RAC1 and downstream signal transduction. Thereby, regulates different biological processes including the organization of the cytoskeleton, cell migration and proliferation. Involved in apoptosis.

Subunit / interactions. Interacts with GPHN and NSF. Interacts with ATG7, ATG13. Interacts with ATG3. Interacts with alpha- and beta-tubulin. Interacts with GABRG2. Interacts with RB1CC1. Interacts with ULK1. Interacts with CALR. Interacts with DDX47. Interacts with TP53INP1 and TP53INP2. Interacts with TBC1D5 and TBC1D25. Directly interacts with SQSTM1. Interacts with MAPK15. Interacts with TECPR2. Interacts with PCM1. Interacts with TRIM5 and TRIM21. Interacts with MEFV. Interacts with KIF21B. Interacts with WDFY3; this interaction is required for WDFY3 recruitment to MAP1LC3B-positive p62/SQSTM1 bodies. Interacts with the reticulophagy receptor TEX264. Interacts with UBA5. Interacts with FLCN; interaction regulates autophagy. Interacts with KBTBD6 and KBTBD7; the interaction is direct and required for the ubiquitination of TIAM1. Interacts with reticulophagy regulators RETREG1, RETREG2 and RETREG3. Interacts with IRGM. Interacts with STX17. Interacts with CT55; this interaction may be important for GABARAP protein stability. Interacts with DNM2. Interacts with NCOA4 (via C-terminus).

Subcellular location. Cytoplasmic vesicle. Autophagosome membrane. Endomembrane system. Cytoplasm. Cytoskeleton. Golgi apparatus membrane.

Tissue specificity. Heart, brain, placenta, liver, skeletal muscle, kidney and pancreas.

Post-translational modifications. The precursor molecule is cleaved by ATG4 (ATG4A, ATG4B, ATG4C or ATG4D) to expose the glycine at the C-terminus and form the cytosolic form, GABARAP-I. The processed form is then activated by APG7L/ATG7, transferred to ATG3 and conjugated to phosphatidylethanolamine (PE) phospholipid to form the membrane-bound form, GABARAP-II. During non-canonical autophagy, the processed form is conjugated to phosphatidylserine (PS) phospholipid. ATG4 proteins also mediate the delipidation of PE-conjugated forms. In addition, ATG4B and ATG4D mediate delipidation of ATG8 proteins conjugated to PS during non-canonical autophagy. ATG4B constitutes the major protein for proteolytic activation. ATG4D is the main enzyme for delipidation activity. (Microbial infection) The Legionella effector RavZ is a deconjugating enzyme that hydrolyzes the amide bond between the C-terminal glycine residue and an adjacent aromatic residue in ATG8 proteins conjugated to phosphatidylethanolamine (PE), producing an ATG8 protein that is resistant to reconjugation by the host machinery due to the cleavage of the reactive C-terminal glycine. RavZ is also able to mediate delipidation of ATG8 proteins conjugated to phosphatidylserine (PS).

Similarity. Belongs to the ATG8 family.

RefSeq proteins (1): NP_009209* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR004241	Atg8-like	Family
IPR029071	Ubiquitin-like_domsf	Homologous_superfamily

Pfam: PF02991

UniProt features (28 total): strand 7, mutagenesis site 6, helix 4, region of interest 4, site 3, lipid moiety-binding region 2, chain 1, propeptide 1

Structure

Experimental structures (PDB)

43 structures, top 30 by resolution.

PDB	Method	Resolution (Å)
6HYO	X-RAY DIFFRACTION	1.07
6YOP	X-RAY DIFFRACTION	1.1
7ZKR	X-RAY DIFFRACTION	1.1
6HYN	X-RAY DIFFRACTION	1.14
7AA8	X-RAY DIFFRACTION	1.25
6HOG	X-RAY DIFFRACTION	1.26
8T2M	X-RAY DIFFRACTION	1.27
3D32	X-RAY DIFFRACTION	1.3
6HB9	X-RAY DIFFRACTION	1.3
7BRQ	X-RAY DIFFRACTION	1.4
9I9X	X-RAY DIFFRACTION	1.42
9HGD	X-RAY DIFFRACTION	1.5
6HOJ	X-RAY DIFFRACTION	1.51
8W6A	X-RAY DIFFRACTION	1.53
7ZL7	X-RAY DIFFRACTION	1.55
6HYL	X-RAY DIFFRACTION	1.56
8T33	X-RAY DIFFRACTION	1.6
6HOK	X-RAY DIFFRACTION	1.61
1GNU	X-RAY DIFFRACTION	1.75
7YO9	X-RAY DIFFRACTION	1.75
7LT6	X-RAY DIFFRACTION	1.8
6HYM	X-RAY DIFFRACTION	1.86
8T2N	X-RAY DIFFRACTION	1.88
4XC2	X-RAY DIFFRACTION	1.9
7BRT	X-RAY DIFFRACTION	2
5DPS	X-RAY DIFFRACTION	2
7BV4	X-RAY DIFFRACTION	2
7VED	X-RAY DIFFRACTION	2.02
8S1M	X-RAY DIFFRACTION	2.05
8T32	X-RAY DIFFRACTION	2.05

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O95166-F1	95.06	0.91

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Catalytic / active sites (3): 17 (interaction with lir (lc3 nteracting region) motif of atg3); 28 (interaction with lir (lc3 nteracting region) motif of atg3); 116–117 (cleavage; by atg4b)

Post-translational modifications (2): 116, 116

Mutagenesis-validated functional residues (6):

Position	Phenotype
24	no effect on wdfy3-binding. impaired wdfy3-binding, but no effect on sqstm1-binding; when associated with h-25 and h-54.
25	no effect on wdfy3-binding. impaired wdfy3-binding, but no effect on sqstm1-binding; when associated with q-24 and h-54.
49–50	inhibits interaction with tecpr2.
54	no effect on wdfy3-binding. impaired wdfy3-binding, but no effect on sqstm1-binding; when associated with q-24 and h-25.
67	no effect on interaction with tecpr2.
116	impairs localization at the autophagosomal membrane.

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-1632852	Macroautophagy
R-HSA-8854214	TBC/RABGAPs

MSigDB gene sets: 341 (showing top): GOBP_REGULATION_OF_PROTEASOMAL_UBIQUITIN_DEPENDENT_PROTEIN_CATABOLIC_PROCESS, GOBP_VACUOLE_ORGANIZATION, BASSO_B_LYMPHOCYTE_NETWORK, GOCC_VACUOLAR_MEMBRANE, MODULE_151, LFA1_Q6, ENK_UV_RESPONSE_KERATINOCYTE_UP, GOBP_POSITIVE_REGULATION_OF_PROTEIN_CATABOLIC_PROCESS, GOBP_PROTEIN_TARGETING, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, GOBP_REGULATION_OF_SMALL_GTPASE_MEDIATED_SIGNAL_TRANSDUCTION, AREB6_01, GOBP_EXTRINSIC_APOPTOTIC_SIGNALING_PATHWAY, REACTOME_MEMBRANE_TRAFFICKING, GGGTGGRR_PAX4_03

GO Biological Process (15): autophagosome assembly (GO:0000045), microtubule cytoskeleton organization (GO:0000226), mitophagy (GO:0000423), protein targeting (GO:0006605), cellular response to nitrogen starvation (GO:0006995), chemical synaptic transmission (GO:0007268), extrinsic apoptotic signaling pathway via death domain receptors (GO:0008625), protein transport (GO:0015031), positive regulation of proteasomal ubiquitin-dependent protein catabolic process (GO:0032436), regulation of Rac protein signal transduction (GO:0035020), autophagosome maturation (GO:0097352), regulation of neurotransmitter receptor localization to postsynaptic specialization membrane (GO:0098696), positive regulation of protein K48-linked ubiquitination (GO:1902524), autophagy (GO:0006914), apoptotic process (GO:0006915)

GO Molecular Function (7): microtubule binding (GO:0008017), phosphatidylethanolamine binding (GO:0008429), ubiquitin protein ligase binding (GO:0031625), beta-tubulin binding (GO:0048487), GABA receptor binding (GO:0050811), protein binding (GO:0005515), phospholipid binding (GO:0005543)

GO Cellular Component (19): Golgi membrane (GO:0000139), autophagosome membrane (GO:0000421), lysosome (GO:0005764), autophagosome (GO:0005776), smooth endoplasmic reticulum (GO:0005790), cytosol (GO:0005829), microtubule (GO:0005874), microtubule associated complex (GO:0005875), plasma membrane (GO:0005886), axoneme (GO:0005930), actin cytoskeleton (GO:0015629), cytoplasmic vesicle (GO:0031410), sperm midpiece (GO:0097225), GABA-ergic synapse (GO:0098982), cytoplasm (GO:0005737), Golgi apparatus (GO:0005794), cytoskeleton (GO:0005856), endomembrane system (GO:0012505), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Autophagy	1
Rab regulation of trafficking	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	6
cytoplasm	3
macroautophagy	2
establishment of protein localization	2
tubulin binding	2
vacuole	2
microtubule cytoskeleton	2
cytoskeleton	2
Atg12 activating enzyme activity	1
protein-phosphatidylethanolamide deconjugating activity	1
Atg12 conjugating enzyme activity	1
Atg12 ligase activity	1
organelle assembly	1
Atg1/ULK1 kinase complex assembly	1
autophagosome organization	1
cytoskeleton organization	1
microtubule-based process	1
autophagy of mitochondrion	1
cellular response to starvation	1
cellular response to nitrogen levels	1
anterograde trans-synaptic signaling	1
extrinsic apoptotic signaling pathway	1
transport	1
intracellular protein localization	1
regulation of proteasomal ubiquitin-dependent protein catabolic process	1
proteasome-mediated ubiquitin-dependent protein catabolic process	1
positive regulation of proteasomal protein catabolic process	1
positive regulation of ubiquitin-dependent protein catabolic process	1
Rac protein signal transduction	1
regulation of small GTPase mediated signal transduction	1
protein-containing complex disassembly	1
regulation of biological quality	1
neurotransmitter receptor localization to postsynaptic specialization membrane	1
regulation of protein localization to synapse	1
regulation of receptor localization to synapse	1
regulation of protein localization to cell periphery	1
regulation of protein localization to membrane	1
regulation of protein K48-linked ubiquitination	1
protein K48-linked ubiquitination	1
positive regulation of protein polyubiquitination	1

Protein interactions and networks

STRING

3365 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
GABARAP	SQSTM1	Q13501	996
GABARAP	NBR1	Q14596	996
GABARAP	BNIP3L	O60238	995
GABARAP	BNIP3	Q12983	994
GABARAP	FUNDC1	Q8IVP5	993
GABARAP	CALCOCO2	Q13137	991
GABARAP	CD300C	Q08708	989
GABARAP	OPTN	Q96CV9	988
GABARAP	ATG3	Q9NT62	982
GABARAP	ATG4B	Q9Y4P1	975
GABARAP	ATG7	O95352	964
GABARAP	ULK1	O75385	958
GABARAP	ATG12	O94817	956
GABARAP	RETREG1	Q9H6L5	952
GABARAP	PLEKHM1	Q9Y4G2	948

IntAct

201 interactions, top by confidence:

A	B	Type	Score
GABARAP	SQSTM1	psi-mi:“MI:0914”(association)	0.950
GABARAP	SQSTM1	psi-mi:“MI:0915”(physical association)	0.950
SQSTM1	GABARAP	psi-mi:“MI:0915”(physical association)	0.950
SQSTM1	GABARAP	psi-mi:“MI:0407”(direct interaction)	0.950
GABARAP	SQSTM1	psi-mi:“MI:0407”(direct interaction)	0.950
GABARAP	NBR1	psi-mi:“MI:0915”(physical association)	0.780
NBR1	GABARAP	psi-mi:“MI:0407”(direct interaction)	0.780
GABARAP	NBR1	psi-mi:“MI:0407”(direct interaction)	0.780
KBTBD6	GABARAP	psi-mi:“MI:0407”(direct interaction)	0.760
GABARAP	KBTBD7	psi-mi:“MI:0407”(direct interaction)	0.760
GABARAP	STBD1	psi-mi:“MI:0407”(direct interaction)	0.760
GABARAP	STBD1	psi-mi:“MI:0915”(physical association)	0.760
KBTBD6	GABARAP	psi-mi:“MI:0915”(physical association)	0.760
KBTBD7	GABARAP	psi-mi:“MI:0915”(physical association)	0.760
KBTBD7	GABARAP	psi-mi:“MI:0914”(association)	0.760
KBTBD6	GABARAP	psi-mi:“MI:0914”(association)	0.760
GABARAP	KBTBD7	psi-mi:“MI:0915”(physical association)	0.760
KBTBD7	GABARAP	psi-mi:“MI:0407”(direct interaction)	0.760
STBD1	GABARAP	psi-mi:“MI:0914”(association)	0.760
GABARAP	PCM1	psi-mi:“MI:0915”(physical association)	0.730

BioGRID (269): MUL1 (Affinity Capture-Western), GABARAP (Affinity Capture-Western), GABARAP (Biochemical Activity), GABARAP (Reconstituted Complex), GABARAP (Reconstituted Complex), GABARAP (Biochemical Activity), GABARAP (Reconstituted Complex), GABARAP (Reconstituted Complex), GABARAP (Affinity Capture-MS), GABARAP (Affinity Capture-MS), GABARAP (Affinity Capture-MS), GABARAP (Two-hybrid), GABARAP (Affinity Capture-Western), GABARAP (FRET), WDFY3 (Affinity Capture-Western)

ESM2 similar proteins: A1CQS1, A1D3N4, A2QPN1, A2XXR7, A2YS06, A4LA70, A6RPU4, A6ZKM4, A7E8H4, A7KAL9, A7TDU7, C4B4E4, I1S1W5, J4UTT5, M1C146, M2SQA5, N4X184, O94272, O95166, P0CO54, P0CO55, P38182, P60517, Q0C804, Q0V3Y9, Q1E4K5, Q2GVL1, Q2UBH5, Q2XPP5, Q4P2U6, Q4WJ27, Q51MW4, Q5B2U9, Q69RC4, Q6C794, Q6FXR8, Q6Z1D5, Q755X2, Q7XPR1, Q8J282

Diamond homologs: A0A1B7XV12, A1CQS1, A1D3N4, A2QPN1, A2XXR7, A2YS06, A3GFU8, A4LA70, A5DWI6, A6NCE7, A6RPU4, A6ZKM4, A7E8H4, A7KAL9, A7TDU7, C4B4E4, I1S1W5, J4UTT5, M1C146, M2SQA5, N4X184, O41515, O94272, O95166, P0C075, P0CO54, P0CO55, P38182, P60517, P60518, P60519, P60520, P60521, P60522, P87068, Q09490, Q0C804, Q0V3Y9, Q0VGK0, Q1E4K5

SIGNOR signaling

12 interactions.

A	Effect	B	Mechanism
O-phosphoethanolamine	up-regulates	GABARAP	“chemical activation”
GABARAP	up-regulates	TBC1D25	binding
NBR1	up-regulates	GABARAP	binding
TP53INP1	up-regulates	GABARAP	binding
GABARAP	“up-regulates activity”	mTORC1	binding
GABARAP	“up-regulates activity”	GPHN	binding
GABARAP	“up-regulates activity”	GABA-A	binding
WDFY3	“down-regulates quantity by destabilization”	GABARAP	binding
ULK1	up-regulates	GABARAP	binding
ANK3	“up-regulates activity”	GABARAP	binding
ATG3	“up-regulates activity”	GABARAP	binding
ATG4B	“up-regulates activity”	GABARAP	cleavage

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 118 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Autophagy	17	30.0×	9e-19
Macroautophagy	21	28.8×	6e-23
PINK1-PRKN Mediated Mitophagy	6	25.5×	8e-06
Selective autophagy	7	23.2×	2e-06
TBC/RABGAPs	7	21.6×	2e-06

GO biological processes:

GO term	Partners	Fold	FDR
piecemeal microautophagy of the nucleus	9	76.6×	1e-13
reticulophagy	8	51.1×	2e-10
mitophagy	17	49.1×	2e-22
autophagosome assembly	21	42.9×	2e-26
macroautophagy	16	35.0×	2e-18
autophagy of mitochondrion	5	33.3×	2e-05
autophagosome maturation	7	22.3×	2e-06
positive regulation of autophagy	9	17.0×	2e-07

Disease & clinical

Clinical variants and AI predictions

ClinVar

7 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	4
Likely benign	0
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

505 predictions. Top by Δscore:

Variant	Effect	Δscore
17:7240918:TC:T	acceptor_gain	1.0000
17:7240919:CC:C	acceptor_gain	1.0000
17:7240920:C:CC	acceptor_gain	1.0000
17:7240925:A:AC	acceptor_gain	1.0000
17:7241339:TACCT:T	donor_loss	1.0000
17:7241340:A:T	donor_loss	1.0000
17:7241456:ACCAA:A	acceptor_gain	1.0000
17:7241457:CCAA:C	acceptor_gain	1.0000
17:7241457:CCAAC:C	acceptor_gain	1.0000
17:7241458:CAA:C	acceptor_gain	1.0000
17:7241458:CAAC:C	acceptor_gain	1.0000
17:7241459:AA:A	acceptor_gain	1.0000
17:7241459:AACTG:A	acceptor_loss	1.0000
17:7241461:C:CC	acceptor_gain	1.0000
17:7241462:T:A	acceptor_loss	1.0000
17:7241462:T:G	acceptor_loss	1.0000
17:7241464:C:CT	acceptor_gain	1.0000
17:7241465:A:T	acceptor_gain	1.0000
17:7241470:A:AC	acceptor_gain	1.0000
17:7241470:A:C	acceptor_gain	1.0000
17:7241473:CAAGA:C	acceptor_gain	1.0000
17:7241474:A:T	acceptor_gain	1.0000
17:7241477:A:C	acceptor_gain	1.0000
17:7241596:CCCAC:C	donor_loss	1.0000
17:7241598:CA:C	donor_loss	1.0000
17:7241677:CAC:C	acceptor_gain	1.0000
17:7242234:T:A	donor_gain	1.0000
17:7240915:TGTTC:T	acceptor_gain	0.9900
17:7240916:GTTC:G	acceptor_gain	0.9900
17:7240917:TTC:T	acceptor_gain	0.9900

AlphaMissense

768 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
17:7241399:A:C	F77L	0.999
17:7241399:A:T	F77L	0.999
17:7241401:A:G	F77L	0.999
17:7241436:C:G	R65P	0.999
17:7241457:C:T	G58D	0.999
17:7241606:A:G	L55P	0.999
17:7241618:A:T	V51E	0.999
17:7241621:A:G	L50P	0.999
17:7241621:A:T	L50Q	0.999
17:7242242:G:T	P30Q	0.999
17:7242248:C:G	R28P	0.999
17:7242279:C:G	G18R	0.999
17:7242291:G:T	R14S	0.999
17:7240894:A:G	L105P	0.998
17:7240904:C:G	D102H	0.998
17:7241458:C:G	G58R	0.998
17:7241625:A:G	Y49H	0.998
17:7241672:A:T	V33E	0.998
17:7241675:A:T	I32K	0.998
17:7241678:A:T	V31E	0.998
17:7242278:C:T	G18D	0.998
17:7240894:A:T	L105H	0.997
17:7240896:A:C	F104L	0.997
17:7240896:A:T	F104L	0.997
17:7240898:A:G	F104L	0.997
17:7240903:T:A	D102V	0.997
17:7241358:A:T	M91K	0.997
17:7241403:A:G	L76S	0.997
17:7241430:C:G	R67P	0.997
17:7241451:A:G	F60S	0.997

dbSNP variants (sampled 300 via entrez): RS1000459012 (17:7240108 A>C,G), RS1000557803 (17:7240386 G>A), RS1001311160 (17:7243687 T>C,G), RS1002182880 (17:7241521 C>T), RS1002502621 (17:7243759 C>G), RS1002575635 (17:7242961 A>T), RS1003310370 (17:7242394 C>G), RS1004287789 (17:7239848 C>G), RS1004320392 (17:7240735 A>G), RS1006338201 (17:7243247 C>T), RS1006885458 (17:7242528 G>A), RS1006988684 (17:7242935 C>A), RS1007039215 (17:7243255 C>T), RS1008987469 (17:7240308 T>A,C), RS1010168127 (17:7243659 G>A)

Disease associations

OMIM: gene MIM:605125 | disease phenotypes:

GenCC curated gene-disease

Mondo (1): breast ductal adenocarcinoma (MONDO:0005590)

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST90013406_268	Liver enzyme levels (alkaline phosphatase)	1.000000e-87

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004533	alkaline phosphatase measurement

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D018270	Carcinoma, Ductal, Breast	C04.557.470.200.025.232.500; C04.557.470.615.132.500; C04.588.180.390; C17.800.090.500.390

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4879423 (SINGLE PROTEIN)

PharmGKB: 1 entry (VIP=true, CPIC=false)

ChEMBL bioactivities

1 potent at pChembl≥5 of 1 total, top 1 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
5.35	IC50	4440	nM	CHEMBL5556385

PubChem BioAssay actives

1 with measured affinity, of 3 total; 1 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
5-(5,6-dichloro-1H-indol-4-yl)-2-[2-(dimethylamino)ethyliminomethyl]-3-hydroxycyclohex-2-en-1-one	2086252: Inhibition of GABARAP (unknown origin) by Alphascreen assay	ic50	4.4400	uM

CTD chemical–gene interactions

30 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
alpha phellandrene	increases expression	1
triphenyl phosphate	affects expression	1
arsenite	affects binding, increases reaction	1
sodium arsenite	increases expression	1
cupric chloride	decreases expression	1
di-n-butylphosphoric acid	affects expression	1
abrine	decreases expression	1
bisphenol S	affects cotreatment, increases expression	1
Resveratrol	increases expression	1
Aspirin	decreases expression	1
Atrazine	decreases expression	1
Benzo(a)pyrene	increases methylation	1
Cadmium	increases expression	1
Carcinogens	decreases expression	1
Dexamethasone	affects cotreatment, increases expression	1
Doxorubicin	decreases expression	1
Ethyl Methanesulfonate	increases expression	1
Formaldehyde	increases expression	1
Hydralazine	affects cotreatment, increases expression	1
Indomethacin	affects cotreatment, increases expression	1
Methyl Methanesulfonate	increases expression	1
Mutagens	decreases expression	1
Sarin	decreases expression, increases expression	1
Tobacco Smoke Pollution	increases expression	1
Tretinoin	increases expression	1
Valproic Acid	increases expression, affects cotreatment	1
1-Methyl-3-isobutylxanthine	affects cotreatment, increases expression	1
Aflatoxin B1	decreases methylation	1
Palmitic Acid	increases metabolic processing	1
Lactic Acid	decreases expression	1

ChEMBL screening assays

3 unique, capped per target: 3 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4835344	Binding	Binding affinity to human GABARAP expressed in Escherichia coli T7 by single site binding model based isothermal titration calorimetry	Demonstrating Ligandability of the LC3A and LC3B Adapter Interface. — J Med Chem

Cellosaurus cell lines

11 cell lines: 11 cancer cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_D7F9	RAW 264.7 Lrrk2 KO + HALO-human LRRK2 + HA-human GABARAP	Cancer cell line	Male
CVCL_E2WX	RAW 264.7 Gabarap KO + HA-human GABARAP	Cancer cell line	Male
CVCL_E2WY	RAW 264.7 Lrrk2 KO + HA-human GABARAP	Cancer cell line	Male
CVCL_E2WZ	RAW 264.7 Lrrk2 KO + HALO-human LRRK2 LIR1 mutant + HA-human GABARAP	Cancer cell line	Male
CVCL_E2X0	RAW 264.7 Lrrk2 KO + HALO-human LRRK2 LIR2 mutant + HA-human GABARAP	Cancer cell line	Male
CVCL_E2X1	RAW 264.7 Lrrk2 KO + HALO-human LRRK2 LIR1+LIR2 mutant + HA-human GABARAP	Cancer cell line	Male
CVCL_SP32	HAP1 GABARAP (-) 1	Cancer cell line	Male
CVCL_SP33	HAP1 GABARAP (-) 2	Cancer cell line	Male
CVCL_SP34	HAP1 GABARAP (-) 3	Cancer cell line	Male
CVCL_SP35	HAP1 GABARAP (-) 4	Cancer cell line	Male

Clinical trials (associated diseases)

11 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT03414970	PHASE3	ACTIVE_NOT_RECRUITING	Hypofractionated Radiation Therapy After Mastectomy in Preventing Recurrence in Patients With Stage IIa-IIIa Breast Cancer
NCT00461344	PHASE2	TERMINATED	Docetaxel + Doxorubicin as Neoadjuvant Chemotherapy in Patients With Breast Cancer
NCT07499999	PHASE2	NOT_YET_RECRUITING	Randomized Double-Blind Phase II Trial of Baby Exemestane Versus Baby Tamoxifen in Post-Menopausal Women at High Risk for Breast Cancer
NCT00637364	PHASE1/PHASE2	SUSPENDED	High Intensity Focused Ultrasound Tumor Treatment for Pancreatic Cancer Pain
NCT02779855	PHASE1/PHASE2	COMPLETED	Talimogene Laherparepvec in Combination With Neoadjuvant Chemotherapy in Triple Negative Breast Cancer
NCT01753908	EARLY_PHASE1	COMPLETED	Broccoli Sprout Extract in Treating Patients With Breast Cancer
NCT01796041	EARLY_PHASE1	COMPLETED	Intraoperative Imaging of Breast Cancer With Indocyanine Green
NCT01208974	Not specified	ACTIVE_NOT_RECRUITING	Nipple-Areola Complex (NAC) Irradiation After Nipple-Sparing Mastectomy and Reconstruction
NCT01875198	Not specified	TERMINATED	Oncologic Impact of Splenectomy-omitting Radical Pancreatectomy in Well-selected Left-sided Pancreatic Cancer
NCT03543397	Not specified	UNKNOWN	MRI in Ductal Carcinoma in Situ (DCIS)
NCT03834532	Not specified	COMPLETED	Living Well After Breast Surgery