GABARAPL2

Summary

GABARAPL2 (GABA type A receptor associated protein like 2, HGNC:13291) is a protein-coding gene on chromosome 16q23.1, encoding Gamma-aminobutyric acid receptor-associated protein-like 2 (P60520). Ubiquitin-like modifier involved in intra-Golgi traffic.

Enables phosphatidylethanolamine binding activity and ubiquitin protein ligase binding activity. Involved in negative regulation of proteasomal protein catabolic process and protein localization to endoplasmic reticulum. Located in Golgi membrane and autophagosome membrane.

Source: NCBI Gene 11345 — RefSeq curated summary.

At a glance

• GWAS associations: 3
• Clinical variants (ClinVar): 14 total
• Druggable target: yes
• MANE Select transcript: NM_007285

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:13291
Approved symbol	GABARAPL2
Name	GABA type A receptor associated protein like 2
Location	16q23.1
Locus type	gene with protein product
Status	Approved
Aliases	GEF2, ATG8, GATE16, GATE-16, ATG8C
Ensembl gene	ENSG00000034713
Ensembl biotype	protein_coding
OMIM	607452
Entrez	11345

Gene structure

Transcript identifiers

Ensembl transcripts: 5 — 4 protein_coding, 1 protein_coding_CDS_not_defined

ENST00000037243, ENST00000563744, ENST00000565057, ENST00000565985, ENST00000568455

RefSeq mRNA: 1 — MANE Select: NM_007285 NM_007285

CCDS: CCDS10921

Canonical transcript exons

ENST00000037243 — 4 exons

Exon	Start	End
ENSE00001143095	75566379	75566520
ENSE00003565779	75568037	75568209
ENSE00003588006	75566852	75566907
ENSE00003629383	75577279	75577881

Expression profiles

Bgee: expression breadth ubiquitous, 302 present calls, max score 99.62.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 73.7132 / max 1172.2812, expressed in 1827 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
155035	73.7132	1827

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
pons	UBERON:0000988	99.62	gold quality
Brodmann (1909) area 46	UBERON:0006483	99.53	gold quality
cerebellar vermis	UBERON:0004720	99.52	gold quality
medial globus pallidus	UBERON:0002477	99.50	gold quality
superior vestibular nucleus	UBERON:0007227	99.49	gold quality
globus pallidus	UBERON:0001875	99.47	gold quality
hypothalamus	UBERON:0001898	99.43	gold quality
subthalamic nucleus	UBERON:0001906	99.43	gold quality
medulla oblongata	UBERON:0001896	99.40	gold quality
spinal cord	UBERON:0002240	99.40	gold quality
adult organism	UBERON:0007023	99.40	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	99.39	gold quality
dorsal plus ventral thalamus	UBERON:0001897	99.37	gold quality
caudate nucleus	UBERON:0001873	99.35	gold quality
nucleus accumbens	UBERON:0001882	99.35	gold quality
paraflocculus	UBERON:0005351	99.35	gold quality
putamen	UBERON:0001874	99.33	gold quality
postcentral gyrus	UBERON:0002581	99.32	gold quality
inferior vagus X ganglion	UBERON:0005363	99.32	gold quality
heart right ventricle	UBERON:0002080	99.31	gold quality
substantia nigra	UBERON:0002038	99.30	gold quality
midbrain	UBERON:0001891	99.27	gold quality
lateral globus pallidus	UBERON:0002476	99.27	gold quality
middle frontal gyrus	UBERON:0002702	99.27	gold quality
amygdala	UBERON:0001876	99.26	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	99.26	gold quality
Brodmann (1909) area 9	UBERON:0013540	99.26	gold quality
dorsal root ganglion	UBERON:0000044	99.21	gold quality
prefrontal cortex	UBERON:0000451	99.21	gold quality
parietal lobe	UBERON:0001872	99.19	gold quality

Single-cell (SCXA)

Detected in 13 experiment(s), a significant marker in 7.

Experiment	Marker?	Max mean expression
E-MTAB-9221	yes	23.68
E-HCAD-10	yes	16.48
E-CURD-46	yes	10.30
E-HCAD-1	yes	9.35
E-CURD-88	yes	5.76
E-HCAD-9	yes	5.57
E-CURD-97	no	508.96
E-MTAB-10042	no	372.31
E-GEOD-124858	no	260.01
E-CURD-120	no	6.14
E-GEOD-125970	no	3.12
E-MTAB-9467	no	2.50
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): E2F1

miRNA regulators (miRDB)

64 targeting GABARAPL2, 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-656-3P	100.00	72.15	2788
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-3658	99.96	73.87	4379
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-651-3P	99.94	73.48	5177
HSA-MIR-145-5P	99.92	71.13	1836
HSA-MIR-5195-3P	99.92	70.92	1877
HSA-MIR-374A-5P	99.90	71.34	2923
HSA-MIR-374B-5P	99.90	69.98	2734
HSA-MIR-5582-3P	99.86	72.48	4221
HSA-MIR-548AR-3P	99.85	71.26	3889
HSA-MIR-3180-5P	99.82	69.12	2422
HSA-MIR-944	99.82	70.85	3042
HSA-MIR-548AZ-3P	99.82	70.56	3549
HSA-MIR-548BC	99.82	70.61	3524
HSA-MIR-548E-3P	99.82	70.59	3514
HSA-MIR-548F-3P	99.82	70.59	3540
HSA-MIR-4639-5P	99.81	67.37	1028
HSA-MIR-374C-5P	99.80	72.06	2910
HSA-MIR-655-3P	99.80	72.19	2909
HSA-MIR-548A-3P	99.76	70.58	3524
HSA-MIR-4255	99.72	67.70	1541
HSA-MIR-4699-3P	99.71	70.15	3142
HSA-MIR-5004-5P	99.68	66.63	1294
HSA-MIR-2053	99.57	69.15	1635
HSA-MIR-105-5P	99.54	69.24	2060
HSA-MIR-7853-5P	99.54	69.30	2055
HSA-MIR-1224-5P	99.48	65.59	803
HSA-MIR-569	99.42	66.32	1009
HSA-MIR-5580-5P	99.38	66.96	1139

Literature-anchored findings (GeneRIF, showing 40)

• Phosphatidylserine and phosphatidylethanolamine are targets of the mammalian Atg8 modifiers, LC3, GABARAP, and GATE-16 (PMID:16303767)
• The results indicate the essential role of the Atg8 system in the proper development of autophagic isolation membranes in mice. (PMID:18768753)
• The autophagy-unrelated association of GFP-LC3 with protein aggregates is dependent on its interaction with p62. (PMID:18776740)
• analysis of human NSF possible binding mode to GABARAP and GATE-16 (PMID:19533740)
• Atg4B possessed the broadest spectrum against all substrates, followed by Atg4A for ATG8 substrates (PMID:21177865)
• The GATE-16 N termini in general and specific residues needed for the fusion activity are essential for the proteins role in autophagosome biogenesis. (PMID:21497758)
• ORP7 negatively regulates GS28 protein stability via sequestration of GATE-16, and may mediate the effect of 25-OH on GS28 and Golgi function. (PMID:21669198)
• The level of GABARAPs is decreased in Lewy body disease. (PMID:21684337)
• identified 14 TBC domain-containing Rab GAPs that bind directly to ATG8 modifiers and that colocalize with LC3-positive autophagy membranes in cells (PMID:22354992)
• TP53INP1, a tumor suppressor, interacts with LC3 and ATG8-family proteins through the LC3-interacting region (LIR) and promotes autophagy-dependent cell death. (PMID:22421968)
• Binding of the Atg1/ULK1 kinase to the ubiquitin-like protein Atg8 regulates autophagy (PMID:22885598)
• Results showed that the mRNA and protein levels of GABARAPL1 and GATE-16 were decreased in the cerebellum of multiple system atrophy relative to controls (PMID:22959883)
• ATG8 proteins act as scaffolds for assembly of the ULK complex at the phagophore (PMID:23043107)
• Legionella pneumophila could interfere with autophagy by using the bacterial effector protein RavZ to directly uncouple Atg8 proteins attached to phosphatidylethanolamine on autophagosome membranes. [RavZ] (PMID:23112293)
• low GABARAPL2/GATE-16 expression is associated with an immature myeloid leukemic phenotype and these proteins are necessary for neutrophil differentiation of APL cells (PMID:23891751)
• these results suggest that TRPML3 plays a role in autophagosome maturation through the interaction with GATE16, by providing Ca(2+) in the fusion process. (PMID:24269818)
• Lipidation of the LC3/GABARAP family of autophagy proteins relies on a membrane-curvature-sensing domain in Atg3. (PMID:24747438)
• describe a protocol for the reconstituted conjugation systems for mammalian Atg8 homologs in vitro using purified recombinant Atg proteins and liposomes. (PMID:25181299)
• Using X-ray crystallography and NMR spectroscopy, the structural transition centered on the C-terminus of GATE-16 protein was identified. (PMID:26284781)
• Cardiolipin interaction with various Atg8 human orthologs, namely LC3B, GABARAPL2 and GABARAP, was investigated. (PMID:27764541)
• Mechanism of cargo-directed Atg8 conjugation during selective autophagy has been described. (PMID:27879200)
• rs12599322 in ATG8 was significantly associated with higher DNA damage levels in Chinese population. (PMID:28512061)
• GABARAPs are identified as the first known direct interaction partners of Nef that are essential for its plasma membrane localization. (PMID:28729737)
• This work defines unique roles for GABARAP and LC3 subfamilies in macroautophagy and selective autophagy and demonstrates how analysis of autophagic machinery in the absence of flux can identify new regulatory circuits. (PMID:29038162)
• Ribophagic flux was not induced upon inhibition of translational elongation or nascent chain uncoupling, but was induced in a comparatively selective manner under proteotoxic stress induced by arsenite (10) or chromosome mis-segregation (11) , dependent upon VPS34 and ATG8 conjugation (PMID:29230017)
• Stx17 directly interacts with IRGM, and efficient Stx17 recruitment to autophagosomes requires IRGM. Both IRGM and Stx17 directly interact with mammalian Atg8 proteins, thus being guided to autophagosomes. (PMID:29420192)
• Study supports the idea that protein levels of parkin associated endothelin like receptor are likely regulated by a multitude of proteins including parkin, protein kinase C interacting protein and gamma-aminobutyrate type A receptor associated protein like 2 via mechanisms that include ubiquitination, proteasomal degradagtion and autophagy. (PMID:29496607)
• This study reveals the important role of SERP1/Ysy6 and Atg8 in endoplasmic reticulum stress response and virulence in Candida albicans. (PMID:29544880)
• GATE-16 regulates TWEAK signaling by Fn14 and thereby NF-kappaB activity. Fn14 accumulates in the ERGIC in absence of GABARAP but within endosomes in the vicinity of autophagic membranes in absence of GATE-16. (PMID:30218067)
• Trim5alpha binds all mammalian ATG8s and that, unlike the typical LC3-interacting region (LIR) that binds to mammalian ATG8s through a beta-strand motif comprising approximately six residues, LC3B binds to Trim5alpha via the alpha-helical coiled-coil region. (PMID:30282803)
• An atypical LIR motif within UBA5 (ubiquitin like modifier activating enzyme 5) interacts with GABARAP proteins and mediates membrane localization of UBA5. (PMID:30990354)
• TEX264, an endoplasmic reticulum (ER)resident protein, remodels subdomainsof the ER into ring-like structures inassociation with ATG8 proteins uponnutrient stress, which then fuse withlysosomes for ER turnover. (PMID:31006537)
• Curvature-sensitive trans-assembly of human Atg8-family proteins in autophagy-related membrane tethering. (PMID:31960529)
• GABARAPL2 Is Critical for Growth Restriction of Toxoplasma gondii in HeLa Cells Treated with Gamma Interferon. (PMID:32094251)
• A PI3K-WIPI2 positive feedback loop allosterically activates LC3 lipidation in autophagy. (PMID:32437499)
• Autophagic Network Analysis of the Dual Effect of Sevoflurane on Neurons Associated with GABARAPL1 and 2. (PMID:32685442)
• Lack of GABARAP-Type Proteins Is Accompanied by Altered Golgi Morphology and Surfaceome Composition. (PMID:33374830)
• Phosphorylation of the LIR Domain of SCOC Modulates ATG8 Binding Affinity and Specificity. (PMID:33845085)
• Non-canonical autophagy drives alternative ATG8 conjugation to phosphatidylserine. (PMID:33909989)
• An ALS-associated variant of the autophagy receptor SQSTM1/p62 reprograms binding selectivity toward the autophagy-related hATG8 proteins. (PMID:34929165)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	gabarapl2	ENSDARG00000027200
mus_musculus	Gabarapl2	ENSMUSG00000031950
rattus_norvegicus	Gabarapl3	ENSRNOG00000019425
rattus_norvegicus		ENSRNOG00000086532
rattus_norvegicus		ENSRNOG00000088238
caenorhabditis_elegans		WBGENE00002981

Paralogs (6): MAP1LC3A (ENSG00000101460), GABARAPL1 (ENSG00000139112), MAP1LC3B (ENSG00000140941), GABARAP (ENSG00000170296), MAP1LC3C (ENSG00000197769), MAP1LC3B2 (ENSG00000258102)

Protein

Protein identifiers

Gamma-aminobutyric acid receptor-associated protein-like 2 — P60520 (reviewed: P60520)

Alternative names: GABA(A) receptor-associated protein-like 2, Ganglioside expression factor 2, General protein transport factor p16, Golgi-associated ATPase enhancer of 16 kDa, MAP1 light chain 3-related protein

All UniProt accessions (4): P60520, H3BQ50, H3BSM5, H3BU36

UniProt curated annotations — full annotation on UniProt →

Function. Ubiquitin-like modifier involved in intra-Golgi traffic. Modulates intra-Golgi transport through coupling between NSF activity and SNAREs activation. It first stimulates the ATPase activity of NSF which in turn stimulates the association with GOSR1. Involved in autophagy. Plays a role in mitophagy which contributes to regulate mitochondrial quantity and quality by eliminating the mitochondria to a basal level to fulfill cellular energy requirements and preventing excess ROS production. Whereas LC3s are involved in elongation of the phagophore membrane, the GABARAP/GATE-16 subfamily is essential for a later stage in autophagosome maturation.

Subunit / interactions. Monomer. Interacts with ATG3, ATG7, ATG13 and ULK1. Interacts with TP53INP1 and TP53INP2. Interacts with TBC1D25. Directly interacts with SQSTM1 and BNIP3. Interacts with TECPR2 and PCM1. Interacts with TBC1D5. Interacts with TRIM5. Interacts with MEFV and TRIM21. Interacts with WDFY3. Interacts with UBA5; promoting recruitment of UBA5 to the endoplasmic reticulum membrane. Interacts with GOSR1. Interacts with KBTBD6 and KBTBD7; the interaction is direct. Interacts with reticulophagy regulators RETREG1, RETREG2 and RETREG3. Interacts with IRGM. Interacts with DNM2. Interacts with NCOA4. Interacts with IRGQ.

Subcellular location. Cytoplasmic vesicle. Autophagosome. Endoplasmic reticulum membrane. Golgi apparatus.

Tissue specificity. Ubiquitous. Expressed at high levels in the brain, heart, prostate, ovary, spleen and skeletal muscle. Expressed at very low levels in lung, thymus and small intestine.

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, GABARAPL2-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, GABARAPL2-II. During non-canonical autophagy, the processed form is conjugated to phosphatidylserine (PS) phospholipid. ATG4 proteins also mediate the delipidation of PE-conjugated forms required for GABARAPL2 recycling when autophagosomes fuse with lysosomes. 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). Phosphorylation at Ser-87 and Ser-88 by TBK1 prevents interaction with ATG4 (ATG4A, ATG4B, ATG4C or ATG4D). Phosphorylation by TBK1 on autophagosomes prevents their delipidation by ATG4 and premature removal from nascent autophagosomes.

Similarity. Belongs to the ATG8 family.

RefSeq proteins (1): NP_009216* (*=MANE)

Domains & families (InterPro)

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

Pfam: PF02991

UniProt features (25 total): mutagenesis site 5, strand 5, helix 4, modified residue 4, lipid moiety-binding region 2, chain 1, propeptide 1, sequence conflict 1, site 1, sequence variant 1

Structure

Experimental structures (PDB)

5 structures.

PDB	Method	Resolution (Å)
8Q6Q	X-RAY DIFFRACTION	1.8
7YO8	X-RAY DIFFRACTION	1.8
7LK3	X-RAY DIFFRACTION	1.9
4CO7	X-RAY DIFFRACTION	2
6H8C	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P60520-F1	94.73	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 (1): 116–117 (cleavage; by atg4)

Post-translational modifications (6): 24, 39, 87, 88, 116, 116

Mutagenesis-validated functional residues (5):

Position	Phenotype
47	strongly reduced interaction with uba5.
87–88	impaired phosphorylation by tbk1.
87–88	phospho-mimetic mutant; impaired interaction with atg4 proteins, preventing cleavage at the c-terminus, conjugation to p
88	phospho-mimetic mutant; abolished localization to autophagosomes.
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: 264 (showing top): GOBP_NEGATIVE_REGULATION_OF_PROTEOLYSIS, MORF_MBD4, GOBP_VACUOLE_ORGANIZATION, MODULE_255, GOCC_VACUOLAR_MEMBRANE, NKX25_02, MODULE_151, ENK_UV_RESPONSE_KERATINOCYTE_UP, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, DARWICHE_SKIN_TUMOR_PROMOTER_UP, DARWICHE_PAPILLOMA_RISK_LOW_UP, DARWICHE_PAPILLOMA_RISK_HIGH_DN, DARWICHE_SQUAMOUS_CELL_CARCINOMA_DN, GOBP_VESICLE_MEDIATED_TRANSPORT, TAL1ALPHAE47_01

GO Biological Process (10): autophagosome assembly (GO:0000045), mitophagy (GO:0000423), intra-Golgi vesicle-mediated transport (GO:0006891), autophagy (GO:0006914), cellular response to nitrogen starvation (GO:0006995), protein transport (GO:0015031), positive regulation of ATP-dependent activity (GO:0032781), protein localization to endoplasmic reticulum (GO:0070972), autophagosome maturation (GO:0097352), negative regulation of proteasomal protein catabolic process (GO:1901799)

GO Molecular Function (9): SNARE binding (GO:0000149), microtubule binding (GO:0008017), phosphatidylethanolamine binding (GO:0008429), ubiquitin protein ligase binding (GO:0031625), beta-tubulin binding (GO:0048487), GABA receptor binding (GO:0050811), ATPase binding (GO:0051117), protein binding (GO:0005515), phospholipid binding (GO:0005543)

GO Cellular Component (10): Golgi membrane (GO:0000139), autophagosome membrane (GO:0000421), cytoplasm (GO:0005737), autophagosome (GO:0005776), endoplasmic reticulum membrane (GO:0005789), Golgi apparatus (GO:0005794), cytosol (GO:0005829), cytoplasmic vesicle (GO:0031410), endoplasmic reticulum (GO:0005783), 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
cytoplasm	4
cellular anatomical structure	3
macroautophagy	2
tubulin binding	2
endomembrane system	2
intracellular membrane-bounded organelle	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
autophagy of mitochondrion	1
Golgi vesicle transport	1
catabolic process	1
transmembrane transport	1
process utilizing autophagic mechanism	1
cellular response to starvation	1
cellular response to nitrogen levels	1
transport	1
intracellular protein localization	1
establishment of protein localization	1
regulation of ATP-dependent activity	1
positive regulation of molecular function	1
ATP-dependent activity	1
protein localization to organelle	1
protein-containing complex disassembly	1
proteasomal protein catabolic process	1
negative regulation of protein catabolic process	1
regulation of proteasomal protein catabolic process	1
protein binding	1
phospholipid binding	1
ubiquitin-like protein ligase binding	1
signaling receptor binding	1
enzyme binding	1
binding	1
lipid binding	1
Golgi apparatus	1
bounding membrane of organelle	1

Protein interactions and networks

STRING

4008 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
GABARAPL2	ATG7	O95352	999
GABARAPL2	ATG3	Q9NT62	999
GABARAPL2	ATG12	O94817	998
GABARAPL2	ATG5	Q9H1Y0	998
GABARAPL2	SQSTM1	Q13501	997
GABARAPL2	NBR1	Q14596	997
GABARAPL2	CALCOCO2	Q13137	991
GABARAPL2	BNIP3L	O60238	990
GABARAPL2	ATG4B	Q9Y4P1	990
GABARAPL2	ULK1	O75385	982
GABARAPL2	CD300C	Q08708	979
GABARAPL2	OPTN	Q96CV9	975
GABARAPL2	SIRT1	Q96EB6	973
GABARAPL2	BNIP3	Q12983	971
GABARAPL2	ATG13	O75143	964

IntAct

426 interactions, top by confidence:

A	B	Type	Score
SQSTM1	GABARAPL2	psi-mi:“MI:0915”(physical association)	0.970
GABARAPL2	SQSTM1	psi-mi:“MI:0915”(physical association)	0.970
GABARAPL2	SQSTM1	psi-mi:“MI:0914”(association)	0.970
UBA5	GABARAPL2	psi-mi:“MI:0915”(physical association)	0.950
GABARAPL2	UBA5	psi-mi:“MI:0915”(physical association)	0.950
TBC1D5	GABARAPL2	psi-mi:“MI:0915”(physical association)	0.800
GABARAPL2	TBC1D5	psi-mi:“MI:0915”(physical association)	0.800
GABARAPL2	CALCOCO2	psi-mi:“MI:0915”(physical association)	0.780
KIAA1958	GABARAPL2	psi-mi:“MI:0915”(physical association)	0.780
TSR2	GABARAPL2	psi-mi:“MI:0915”(physical association)	0.780
CALCOCO2	GABARAPL2	psi-mi:“MI:0915”(physical association)	0.780
GABARAPL2	KIAA1958	psi-mi:“MI:0915”(physical association)	0.780
GABARAPL2	TSR2	psi-mi:“MI:0915”(physical association)	0.780
GABARAPL2	MLX	psi-mi:“MI:0915”(physical association)	0.740
MLX	GABARAPL2	psi-mi:“MI:0915”(physical association)	0.740
GABARAPL2	TBC1D25	psi-mi:“MI:0915”(physical association)	0.740
GABARAPL2	RCN2	psi-mi:“MI:0915”(physical association)	0.740
KRTAP10-7	GABARAPL2	psi-mi:“MI:0915”(physical association)	0.720
GABARAPL2	TNIP1	psi-mi:“MI:0915”(physical association)	0.720

BioGRID (289): GABARAPL2 (Two-hybrid), GABARAPL2 (Two-hybrid), GABARAPL2 (Two-hybrid), GABARAPL2 (Two-hybrid), GABARAPL2 (Two-hybrid), TBC1D9B (Two-hybrid), SIK2 (Two-hybrid), BCL2L13 (Two-hybrid), ARFGAP1 (Two-hybrid), AGTRAP (Two-hybrid), CALCOCO1 (Two-hybrid), UBA5 (Two-hybrid), TSR2 (Two-hybrid), AHNAK2 (Two-hybrid), FUNDC1 (Two-hybrid)

ESM2 similar proteins: A1CQS1, A1D3N4, A2XXR7, A2YAG8, A2YS06, A6NCE7, A6RPU4, A7KAL9, I1S1W5, J4UTT5, M1C146, M2SQA5, N4X184, O41515, P0CM28, P0CM29, P60519, P60520, P60521, P60522, Q0C804, Q0V3Y9, Q1E4K5, Q1SF86, Q2HJ23, Q2RBS4, Q2UBH5, Q2XPP5, Q4P2U6, Q4WJ27, Q69NP0, Q69RC4, Q6XVN8, Q6Z1D5, Q7XPR1, Q86CR8, Q8J282, Q8LEM4, Q8S924, Q8S925

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

7 interactions.

A	Effect	B	Mechanism
GABARAPL2	“up-regulates activity”	SQSTM1	binding
TP53INP2	up-regulates	GABARAPL2	binding
NBR1	up-regulates	GABARAPL2	binding
TP53INP1	up-regulates	GABARAPL2	binding
ATG3	“up-regulates activity”	GABARAPL2	binding
ATG4B	“up-regulates activity”	GABARAPL2	cleavage
ATG7	“up-regulates activity”	GABARAPL2	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 92 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
AUF1 (hnRNP D0) binds and destabilizes mRNA	5	18.2×	1e-03
Hedgehog ligand biogenesis	5	15.6×	1e-03
Regulation of PTEN stability and activity	5	13.5×	2e-03
Orc1 removal from chromatin	5	13.1×	2e-03
Assembly of the pre-replicative complex	6	12.3×	1e-03
Hedgehog ‘on’ state	5	11.7×	3e-03
Macroautophagy	6	10.2×	2e-03
MAPK6/MAPK4 signaling	5	10.0×	3e-03

GO biological processes:

GO term	Partners	Fold	FDR
mitophagy	8	29.2×	2e-07
autophagosome assembly	5	12.9×	6e-03
autophagy	7	8.9×	3e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	8
Likely benign	0
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

305 predictions. Top by Δscore:

Variant	Effect	Δscore
16:75566516:GCTGG:G	donor_gain	1.0000
16:75566518:TGG:T	donor_gain	1.0000
16:75566518:TGGGT:T	donor_loss	1.0000
16:75566519:GG:G	donor_gain	1.0000
16:75566519:GGG:G	donor_gain	1.0000
16:75566520:GG:G	donor_gain	1.0000
16:75566521:G:GG	donor_gain	1.0000
16:75566521:GTA:G	donor_loss	1.0000
16:75566850:A:AG	acceptor_gain	1.0000
16:75566851:G:GG	acceptor_gain	1.0000
16:75566906:CGGT:C	donor_loss	1.0000
16:75566908:G:GA	donor_loss	1.0000
16:75566908:G:GG	donor_gain	1.0000
16:75566909:T:G	donor_loss	1.0000
16:75568034:CAG:C	acceptor_loss	1.0000
16:75568036:GGT:G	acceptor_gain	1.0000
16:75577277:A:G	acceptor_gain	1.0000
16:75566505:G:GT	donor_gain	0.9900
16:75566517:CTGG:C	donor_gain	0.9900
16:75566847:CACA:C	acceptor_loss	0.9900
16:75566849:CAGA:C	acceptor_loss	0.9900
16:75566851:G:GC	acceptor_loss	0.9900
16:75566851:GAA:G	acceptor_gain	0.9900
16:75566851:GAAC:G	acceptor_gain	0.9900
16:75566910:GA:G	donor_loss	0.9900
16:75568035:A:AG	acceptor_gain	0.9900
16:75568035:AGGT:A	acceptor_gain	0.9900
16:75568036:G:GT	acceptor_gain	0.9900
16:75568036:GGTG:G	acceptor_gain	0.9900
16:75568036:GGTGA:G	acceptor_gain	0.9900

AlphaMissense

773 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
16:75568098:T:A	V51D	0.999
16:75568140:G:C	R65T	0.999
16:75568140:G:T	R65M	0.999
16:75568175:T:C	F77L	0.999
16:75568177:C:A	F77L	0.999
16:75568177:C:G	F77L	0.999
16:75577325:T:C	F104L	0.999
16:75577327:C:A	F104L	0.999
16:75577327:C:G	F104L	0.999
16:75566858:G:C	R14T	0.998
16:75566859:A:C	R14S	0.998
16:75566859:A:T	R14S	0.998
16:75566906:C:A	P30Q	0.998
16:75568044:T:A	V33E	0.998
16:75568090:G:C	K48N	0.998
16:75568090:G:T	K48N	0.998
16:75568095:T:C	L50S	0.998
16:75568125:T:C	F60S	0.998
16:75568137:T:A	I64N	0.998
16:75568141:G:C	R65S	0.998
16:75568141:G:T	R65S	0.998
16:75568146:G:T	R67M	0.998
16:75568147:G:C	R67S	0.998
16:75568147:G:T	R67S	0.998
16:75577326:T:C	F104S	0.998
16:75566499:T:C	F5L	0.997
16:75566501:C:A	F5L	0.997
16:75566501:C:G	F5L	0.997
16:75566900:G:T	R28M	0.997
16:75568038:T:A	V31E	0.997

dbSNP variants (sampled 300 via entrez): RS1000633577 (16:75566319 G>A,T), RS1000684617 (16:75577088 G>T), RS1000793207 (16:75571836 C>T), RS1000986187 (16:75564594 C>G,T), RS1001166473 (16:75571592 A>C), RS1001605958 (16:75564894 A>T), RS1001635504 (16:75565228 C>A,T), RS1001657416 (16:75575600 C>T), RS1001750559 (16:75574621 T>C), RS1001796288 (16:75574747 C>T), RS1002005469 (16:75570076 T>A), RS1002147355 (16:75564974 T>A,G), RS1002199341 (16:75570572 C>G), RS1002609261 (16:75571920 C>G,T), RS1002720085 (16:75566615 C>T)

Disease associations

OMIM: gene MIM:607452 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

3 associations (top):

Study	Trait	p-value
GCST002553_10	Pancreatic cancer	1.000000e-10
GCST006585_2575	Blood protein levels	2.000000e-08
GCST90000047_217	Age at first sexual intercourse	6.000000e-09

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0009749	age at first sexual intercourse measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4879445 (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
6.07	IC50	860	nM	CHEMBL5556385

PubChem BioAssay actives

1 with measured affinity, of 2 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	2086254: Inhibition of GABARAPL2 (unknown origin) by Alphascreen assay	ic50	0.8600	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	affects cotreatment, increases expression, decreases expression, increases abundance	4
Particulate Matter	increases abundance, increases expression	2
aristolochic acid I	increases expression	1
dicrotophos	decreases expression	1
triphenyl phosphate	affects expression	1
lead acetate	increases expression, affects cotreatment	1
trichostatin A	affects expression	1
manganese chloride	increases expression, affects cotreatment, increases abundance	1
perfluorooctane sulfonic acid	increases expression	1
trovafloxacin	decreases reaction, increases expression	1
CGP 52608	affects binding, increases reaction	1
perfluoro-n-nonanoic acid	increases expression	1
corosolic acid	increases expression	1
(4-amino-1,4-dihydro-3-(2-pyridyl)-5-thioxo-1,2,4-triazole)copper(II)	increases expression	1
Arsenic Trioxide	increases expression	1
Acetaminophen	increases expression	1
Air Pollutants	increases abundance, increases expression	1
Arsenic	affects cotreatment, increases abundance, increases expression	1
Vehicle Emissions	increases abundance, increases expression	1
Chloroquine	increases expression	1
Cisplatin	increases expression	1
Clozapine	increases expression	1
Ethyl Methanesulfonate	increases expression	1
Manganese	increases abundance, increases expression, affects cotreatment	1
Methyl Methanesulfonate	increases expression	1
Tretinoin	increases expression	1
Valproic Acid	increases expression	1
Zinc	affects expression	1
Cyclosporine	decreases expression	1
Aflatoxin B1	decreases methylation, increases expression	1

ChEMBL screening assays

2 unique, capped per target: 2 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4835346	Binding	Binding affinity to human GABARAPL2 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

2 cell lines: 2 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_SP39	HAP1 GABARAPL2 (-) 1	Cancer cell line	Male
CVCL_SP40	HAP1 GABARAPL2 (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

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