NEURL1B

Summary

NEURL1B (neuralized E3 ubiquitin protein ligase 1B, HGNC:35422) is a protein-coding gene on chromosome 5q35.1, encoding E3 ubiquitin-protein ligase NEURL1B (A8MQ27). E3 ubiquitin-protein ligase involved in regulation of the Notch pathway through influencing the stability and activity of several Notch ligands.

Predicted to enable ubiquitin protein ligase activity. Predicted to be involved in ubiquitin-dependent endocytosis. Located in actin cytoskeleton and cytosol.

Source: NCBI Gene 54492 — RefSeq curated summary.

At a glance

• GWAS associations: 2
• Clinical variants (ClinVar): 88 total
• MANE Select transcript: NM_001142651

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:35422
Approved symbol	NEURL1B
Name	neuralized E3 ubiquitin protein ligase 1B
Location	5q35.1
Locus type	gene with protein product
Status	Approved
Aliases	DKFZP761M1511, Neur2, RNF67B
Ensembl gene	ENSG00000214357
Ensembl biotype	protein_coding
OMIM	615893
Entrez	54492

Gene structure

Transcript identifiers

Ensembl transcripts: 4 — 4 protein_coding

ENST00000369800, ENST00000520919, ENST00000522853, ENST00000857825

RefSeq mRNA: 3 — MANE Select: NM_001142651 NM_001142651, NM_001308177, NM_001308178

CCDS: CCDS47342, CCDS78085, CCDS83042

Canonical transcript exons

ENST00000369800 — 5 exons

Exon	Start	End
ENSE00001450939	172683419	172684138
ENSE00001531985	172686681	172691540
ENSE00001531986	172686171	172686296
ENSE00001531987	172669785	172670330
ENSE00003893176	172641263	172641437

Expression profiles

Bgee: expression breadth ubiquitous, 244 present calls, max score 99.19.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 6.7779 / max 154.4001, expressed in 994 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
60206	6.7779	994

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
ileal mucosa	UBERON:0000331	99.19	gold quality
left ventricle myocardium	UBERON:0006566	98.00	gold quality
seminal vesicle	UBERON:0000998	97.04	gold quality
upper arm skin	UBERON:0004263	96.82	gold quality
corpus epididymis	UBERON:0004359	96.44	gold quality
cardiac muscle of right atrium	UBERON:0003379	96.09	gold quality
cauda epididymis	UBERON:0004360	94.90	gold quality
pericardium	UBERON:0002407	94.83	gold quality
lower lobe of lung	UBERON:0008949	94.72	gold quality
parietal pleura	UBERON:0002400	94.61	gold quality
skin of hip	UBERON:0001554	93.66	gold quality
visceral pleura	UBERON:0002401	93.65	gold quality
caput epididymis	UBERON:0004358	92.88	gold quality
myocardium	UBERON:0002349	92.85	gold quality
tibialis anterior	UBERON:0001385	92.74	gold quality
urethra	UBERON:0000057	92.70	gold quality
upper leg skin	UBERON:0004262	92.31	gold quality
tendon of biceps brachii	UBERON:0008188	92.10	gold quality
saphenous vein	UBERON:0007318	91.98	gold quality
superficial temporal artery	UBERON:0001614	91.94	gold quality
colonic mucosa	UBERON:0000317	91.73	gold quality
apex of heart	UBERON:0002098	91.47	gold quality
layer of synovial tissue	UBERON:0007616	91.06	gold quality
heart right ventricle	UBERON:0002080	90.81	gold quality
mucosa of sigmoid colon	UBERON:0004993	90.61	gold quality
cortical plate	UBERON:0005343	90.18	gold quality
nipple	UBERON:0002030	89.92	gold quality
penis	UBERON:0000989	89.83	gold quality
left uterine tube	UBERON:0001303	89.07	gold quality
vena cava	UBERON:0004087	89.06	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	6.52
E-MTAB-6678	no	2.41

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

221 targeting NEURL1B, 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-7110-3P	100.00	73.18	2486
HSA-MIR-6873-3P	100.00	71.42	2626
HSA-MIR-30A-5P	100.00	76.31	3233
HSA-MIR-30B-5P	100.00	76.29	3248
HSA-MIR-30C-5P	100.00	76.29	3248
HSA-MIR-30D-5P	100.00	76.32	3233
HSA-MIR-30E-5P	100.00	76.32	3242
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-6833-3P	100.00	70.63	3197
HSA-MIR-4768-5P	100.00	69.49	2861
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-4262	100.00	73.26	3931
HSA-MIR-4673	100.00	66.64	1490
HSA-MIR-4476	100.00	68.18	2030
HSA-MIR-5193	100.00	67.26	1744
HSA-MIR-4747-5P	100.00	67.90	2681
HSA-MIR-5196-5P	100.00	67.98	2761
HSA-MIR-6876-5P	100.00	67.68	2126
HSA-MIR-4533	100.00	69.48	2758
HSA-MIR-4283	100.00	66.42	2097
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-181A-5P	99.99	72.96	2995
HSA-MIR-181B-5P	99.99	72.97	2996
HSA-MIR-181C-5P	99.99	72.95	2996
HSA-MIR-181D-5P	99.99	73.04	2997
HSA-MIR-1184	99.99	68.19	1458
HSA-MIR-10401-5P	99.99	65.79	948
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-27A-3P	99.98	72.13	2955
HSA-MIR-27B-3P	99.98	72.13	2955

Literature-anchored findings (GeneRIF, showing 1)

• Neur2, in contrast to Neur1, is highly expressed during embryonic development of the brain and several non-neural tissues and its mRNA levels subside postnatally. (PMID:19723503)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	neurl1b	ENSDARG00000099694
mus_musculus	Neurl1b	ENSMUSG00000034413
rattus_norvegicus	Neurl1b	ENSRNOG00000027606

Paralogs (3): NEURL1 (ENSG00000107954), NEURL3 (ENSG00000163121), NEURL4 (ENSG00000215041)

Protein

Protein identifiers

E3 ubiquitin-protein ligase NEURL1B — A8MQ27 (reviewed: A8MQ27)

Alternative names: Neuralized-2, Neuralized-like protein 1B, Neuralized-like protein 3, RING-type E3 ubiquitin transferase NEURL1B

All UniProt accessions (1): A8MQ27

UniProt curated annotations — full annotation on UniProt →

Function. E3 ubiquitin-protein ligase involved in regulation of the Notch pathway through influencing the stability and activity of several Notch ligands.

Subunit / interactions. Interacts with JAG1, DLL1 and DLL4.

Subcellular location. Cytoplasm.

Tissue specificity. Highest expression in brain, prostate and small intestine. In the brain the levels are higher in fetal than in adult stage. In the adult brain the highest levels are detected in the olfactory system, cerebellar cortex, optic nerve and the frontal lobe.

Pathway. Protein modification; protein ubiquitination.

Isoforms (3)

UniProt ID	Names	Canonical?
A8MQ27-1	1	yes
A8MQ27-2	2, delta-NHR1
A8MQ27-3	3, delta-NHR2

RefSeq proteins (3): NP_001136123, NP_001295106, NP_001295107 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001841	Znf_RING	Domain
IPR006573	NHR_dom	Domain
IPR013083	Znf_RING/FYVE/PHD	Homologous_superfamily
IPR037962	Neuralized	Family
IPR043136	B30.2/SPRY_sf	Homologous_superfamily

Pfam: PF07177, PF13920

UniProt features (10 total): domain 2, compositionally biased region 2, splice variant 2, chain 1, zinc finger region 1, region of interest 1, modified residue 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-A8MQ27-F1	71.93	0.33

Functional residue map

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

Post-translational modifications (1): 199

Function

Pathways and Gene Ontology

Reactome pathways

17 pathways

ID	Pathway
R-HSA-2122948	Activated NOTCH1 Transmits Signal to the Nucleus
R-HSA-2644606	Constitutive Signaling by NOTCH1 PEST Domain Mutants
R-HSA-2691232	Constitutive Signaling by NOTCH1 HD Domain Mutants
R-HSA-2894862	Constitutive Signaling by NOTCH1 HD+PEST Domain Mutants
R-HSA-2979096	NOTCH2 Activation and Transmission of Signal to the Nucleus
R-HSA-9013507	NOTCH3 Activation and Transmission of Signal to the Nucleus
R-HSA-157118	Signaling by NOTCH
R-HSA-162582	Signal Transduction
R-HSA-1643685	Disease
R-HSA-1980143	Signaling by NOTCH1
R-HSA-1980145	Signaling by NOTCH2
R-HSA-2644602	Signaling by NOTCH1 PEST Domain Mutants in Cancer
R-HSA-2644603	Signaling by NOTCH1 in Cancer
R-HSA-2691230	Signaling by NOTCH1 HD Domain Mutants in Cancer
R-HSA-2894858	Signaling by NOTCH1 HD+PEST Domain Mutants in Cancer
R-HSA-5663202	Diseases of signal transduction by growth factor receptors and second messengers
R-HSA-9012852	Signaling by NOTCH3

MSigDB gene sets: 163 (showing top): REACTOME_SIGNALING_BY_NOTCH, GOBP_VESICLE_MEDIATED_TRANSPORT, GOBP_ESTABLISHMENT_OF_PROTEIN_LOCALIZATION_TO_ORGANELLE, GOBP_POST_TRANSLATIONAL_PROTEIN_MODIFICATION, GOBP_PROTEIN_LOCALIZATION_TO_ORGANELLE, CERVERA_SDHB_TARGETS_1_UP, GOBP_IMPORT_INTO_CELL, GOBP_ENDOCYTOSIS, NAKAMURA_TUMOR_ZONE_PERIPHERAL_VS_CENTRAL_UP, LINDGREN_BLADDER_CANCER_CLUSTER_1_DN, GOMF_ACYLTRANSFERASE_ACTIVITY, GOMF_AMINOACYLTRANSFERASE_ACTIVITY, GOMF_UBIQUITIN_LIKE_PROTEIN_LIGASE_ACTIVITY, LIU_PROSTATE_CANCER_DN, MIYAGAWA_TARGETS_OF_EWSR1_ETS_FUSIONS_UP

GO Biological Process (3): Notch signaling pathway (GO:0007219), protein ubiquitination (GO:0016567), ubiquitin-dependent endocytosis (GO:0070086)

GO Molecular Function (5): zinc ion binding (GO:0008270), ubiquitin protein ligase activity (GO:0061630), protein binding (GO:0005515), transferase activity (GO:0016740), metal ion binding (GO:0046872)

GO Cellular Component (4): early endosome (GO:0005769), cytosol (GO:0005829), actin cytoskeleton (GO:0015629), cytoplasm (GO:0005737)

Reactome top-level categories

Rollup of top-11 pathways:

Category	Pathways
Signaling by NOTCH	3
Signaling by NOTCH1 in Cancer	3
Signaling by NOTCH1	1
Signaling by NOTCH1 PEST Domain Mutants in Cancer	1
Signaling by NOTCH1 HD Domain Mutants in Cancer	1
Signaling by NOTCH1 HD+PEST Domain Mutants in Cancer	1
Signaling by NOTCH2	1
Signaling by NOTCH3	1
Signal Transduction	1
Diseases of signal transduction by growth factor receptors and second messengers	1
Disease	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	2
cell surface receptor signaling pathway	1
protein modification by small protein conjugation	1
endocytosis	1
protein transport	1
protein localization to organelle	1
establishment of protein localization to organelle	1
transition metal ion binding	1
ubiquitin-protein transferase activity	1
ubiquitin-like protein ligase activity	1
binding	1
catalytic activity	1
cation binding	1
endosome	1
cytoplasm	1
cytoskeleton	1
intracellular anatomical structure	1

Protein interactions and networks

STRING

1039 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
NEURL1B	JAG1	P78504	537
NEURL1B	KLHL38	Q2WGJ6	520
NEURL1B	MIB2	Q96AX9	510
NEURL1B	MRPL15	Q9P015	487
NEURL1B	ACTR6	Q9GZN1	486
NEURL1B	NCAN	O14594	447
NEURL1B	ZNRF1	Q8ND25	414
NEURL1B	TUBGCP2	Q9BSJ2	410
NEURL1B	CROCC2	H7BZ55	409
NEURL1B	CALN1	Q9BXU9	408
NEURL1B	FAM43A	Q8N2R8	406
NEURL1B	RAPSN	Q13702	390
NEURL1B	RITA1	Q96K30	389
NEURL1B	PDZD11	Q5EBL8	386
NEURL1B	SKP2	Q13309	362

IntAct

2 interactions, top by confidence:

A	B	Type	Score
KRT40	NEURL1B	psi-mi:“MI:0914”(association)	0.350

BioGRID (8): NEURL1B (Affinity Capture-Western), NEURL1B (Affinity Capture-RNA), NEURL1B (Affinity Capture-MS), NEURL1B (Affinity Capture-RNA), Dll1 (Affinity Capture-Western), Dll4 (Affinity Capture-Western), Dll1 (Co-localization), Dll4 (Co-localization)

ESM2 similar proteins: A5PJU7, A8MQ27, F1MLB4, F1MX48, F1SAM7, I3L5V6, O75425, O95382, P36916, Q08DG4, Q0MW30, Q14451, Q2YD98, Q32P44, Q3MIP1, Q3T033, Q3UPE3, Q3UV16, Q505F5, Q5EBM0, Q5U651, Q5ZM20, Q641Q3, Q6MG06, Q6SZW1, Q6ZTW0, Q7T0L4, Q8BGG6, Q8BH83, Q8C0R7, Q8K0Y7, Q8N9W5, Q8R2K4, Q8TE68, Q8VC03, Q96BM1, Q96E14, Q96EF6, Q96EY9, Q99JB7

Diamond homologs: A1L020, A1L3F4, A8MQ27, A9JTP3, A9ULZ2, P41436, Q05A36, Q0MW30, Q13490, Q3UE17, Q5U5Q3, Q62210, Q69Z36, Q6ZN04, Q86XN8, Q8JHV9, Q90660, Q9SYH3, O60291, O76050, Q0WS06, Q3TEL6, Q4FE47, Q557E7, Q5M870, Q5XIQ4, Q6INH1, Q6R7D2, Q7ZUL9, Q84ME1, Q8CJC5, Q8VCM5, Q923S6, Q94HV7, Q96EH8, Q96PX1, Q9BR09, Q9D074, Q9D0S4, M0R5D6

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
Ub:E2	“up-regulates activity”	NEURL1B	ubiquitination

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	82
Likely benign	1
Benign	1

Top pathogenic / likely-pathogenic (0)

SpliceAI

895 predictions. Top by Δscore:

Variant	Effect	Δscore
5:172641434:CCAGG:C	donor_loss	1.0000
5:172641436:AGGT:A	donor_loss	1.0000
5:172641437:GGTAC:G	donor_loss	1.0000
5:172641438:G:GA	donor_loss	1.0000
5:172641439:T:A	donor_loss	1.0000
5:172670329:GG:G	donor_gain	1.0000
5:172670330:GG:G	donor_gain	1.0000
5:172670331:G:GA	donor_loss	1.0000
5:172670332:TAG:T	donor_loss	1.0000
5:172686166:CTCA:C	acceptor_loss	1.0000
5:172686167:TCAG:T	acceptor_loss	1.0000
5:172686168:CAGGT:C	acceptor_loss	1.0000
5:172686169:AGGT:A	acceptor_loss	1.0000
5:172686293:CTGGG:C	donor_loss	1.0000
5:172686294:TGGG:T	donor_loss	1.0000
5:172686295:GG:G	donor_gain	1.0000
5:172686296:GG:G	donor_gain	1.0000
5:172686297:G:GA	donor_loss	1.0000
5:172686297:G:GG	donor_gain	1.0000
5:172686298:T:A	donor_loss	1.0000
5:172686675:C:CA	acceptor_gain	1.0000
5:172686676:G:A	acceptor_gain	1.0000
5:172686677:GCA:G	acceptor_loss	1.0000
5:172686678:CAG:C	acceptor_loss	1.0000
5:172686679:A:AG	acceptor_gain	1.0000
5:172686679:AGT:A	acceptor_gain	1.0000
5:172686679:AGTGA:A	acceptor_loss	1.0000
5:172686680:G:GA	acceptor_gain	1.0000
5:172686680:GT:G	acceptor_gain	1.0000
5:172686680:GTG:G	acceptor_gain	1.0000

AlphaMissense

3538 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
5:172669875:T:C	F41S	1.000
5:172669892:G:C	G47R	1.000
5:172669893:G:T	G47V	1.000
5:172669929:C:A	A59D	1.000
5:172669946:T:C	F65L	1.000
5:172669948:C:A	F65L	1.000
5:172669948:C:G	F65L	1.000
5:172669956:G:A	G68D	1.000
5:172669965:T:C	F71S	1.000
5:172669968:C:A	T72K	1.000
5:172670004:T:C	L84P	1.000
5:172670049:T:C	F99S	1.000
5:172670051:G:C	G100R	1.000
5:172670052:G:A	G100D	1.000
5:172670052:G:T	G100V	1.000
5:172670055:T:C	F101S	1.000
5:172670070:C:A	P106Q	1.000
5:172670103:A:G	Y117C	1.000
5:172670106:C:A	A118D	1.000
5:172670108:T:C	C119R	1.000
5:172670118:T:C	L122P	1.000
5:172670142:C:A	A130D	1.000
5:172670189:T:G	Y146D	1.000
5:172670282:T:A	W177R	1.000
5:172670282:T:C	W177R	1.000
5:172670284:G:C	W177C	1.000
5:172670284:G:T	W177C	1.000
5:172670294:G:C	D181H	1.000
5:172670295:A:T	D181V	1.000
5:172670303:G:C	G184R	1.000

dbSNP variants (sampled 300 via entrez): RS1000133670 (5:172662165 A>T), RS1000147425 (5:172648185 C>A), RS1000157376 (5:172648548 C>T), RS1000245332 (5:172677937 C>T), RS1000364054 (5:172654715 C>T), RS1000421985 (5:172641785 T>G), RS1000480259 (5:172674547 T>G), RS1000578737 (5:172687042 G>A), RS1000721025 (5:172653470 T>G), RS1000732579 (5:172650947 A>G), RS1000760733 (5:172658914 C>A,G), RS1000797863 (5:172669829 G>A,C), RS1000852383 (5:172674732 T>G), RS1000854612 (5:172658735 C>T), RS1000894098 (5:172670233 C>T)

Disease associations

OMIM: gene MIM:615893 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST002575_2	Body mass index (change over time)	5.000000e-07
GCST002575_6	Body mass index (change over time)	9.000000e-08

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0005937	longitudinal BMI measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
trichostatin A	affects cotreatment, decreases expression, increases expression	3
sodium arsenite	decreases expression, increases expression	3
Valproic Acid	affects expression, increases expression	3
Aflatoxin B1	increases expression, increases methylation	3
Particulate Matter	decreases expression, increases abundance	3
bisphenol A	increases expression, decreases expression	2
Air Pollutants	decreases expression, increases abundance	2
Benzo(a)pyrene	affects methylation, decreases methylation, increases expression	2
Phenylmercuric Acetate	affects cotreatment, decreases expression	2
Tobacco Smoke Pollution	decreases expression	2
aristolochic acid I	decreases expression	1
propionaldehyde	decreases expression	1
arsenite	affects binding, decreases reaction	1
zinc chromate	decreases expression, increases abundance	1
benzo(e)pyrene	increases methylation	1
2,3-bis(3’-hydroxybenzyl)butyrolactone	affects cotreatment, increases expression	1
aflatoxin B2	increases methylation	1
cupric chloride	decreases expression	1
hydroquinone	increases expression	1
S-(1,2-dichlorovinyl)cysteine	affects response to substance, increases expression, affects cotreatment, decreases expression	1
diallyl trisulfide	decreases expression	1
dinophysistoxin 1	decreases expression	1
chromium hexavalent ion	decreases expression, increases abundance	1
entinostat	increases expression	1
monomethylarsonous acid	decreases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
ICG 001	increases expression	1
abrine	decreases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
enzalutamide	affects expression	1

Clinical trials (associated diseases)

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