LDLRAD3

Summary

LDLRAD3 (low density lipoprotein receptor class A domain containing 3, HGNC:27046) is a protein-coding gene on chromosome 11p13, encoding Low-density lipoprotein receptor class A domain-containing protein 3 (Q86YD5). May influence APP processing, resulting in a decrease in sAPP-alpha production and increased amyloidogenic P3 peptide production.

Predicted to enable amyloid-beta binding activity. Predicted to be involved in receptor-mediated endocytosis. Predicted to act upstream of or within regulation of protein processing. Predicted to be located in endomembrane system and membrane. Predicted to be active in plasma membrane.

Source: NCBI Gene 143458 — RefSeq curated summary.

At a glance

• GWAS associations: 4
• Clinical variants (ClinVar): 61 total
• MANE Select transcript: NM_174902

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:27046
Approved symbol	LDLRAD3
Name	low density lipoprotein receptor class A domain containing 3
Location	11p13
Locus type	gene with protein product
Status	Approved
Aliases	LRAD3
Ensembl gene	ENSG00000179241
Ensembl biotype	protein_coding
OMIM	617986
Entrez	143458

Gene structure

Transcript identifiers

Ensembl transcripts: 10 — 7 protein_coding, 3 protein_coding_CDS_not_defined

ENST00000315571, ENST00000524419, ENST00000528989, ENST00000529759, ENST00000532490, ENST00000534091, ENST00000872890, ENST00000872891, ENST00000872892, ENST00000913841

RefSeq mRNA: 3 — MANE Select: NM_174902 NM_001304263, NM_001304264, NM_174902

CCDS: CCDS31462, CCDS76394

Canonical transcript exons

ENST00000315571 — 6 exons

Exon	Start	End
ENSE00001254210	36229160	36232136
ENSE00001313696	36036103	36036249
ENSE00001371974	35944062	35944144
ENSE00003468417	36098327	36098461
ENSE00003562983	36081653	36081778
ENSE00003658795	36227085	36227430

Expression profiles

Bgee: expression breadth ubiquitous, 237 present calls, max score 94.24.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 10.6176 / max 140.9170, expressed in 1644 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
113877	10.6176	1644

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
parotid gland	UBERON:0001831	94.24	gold quality
medial globus pallidus	UBERON:0002477	94.18	gold quality
ventricular zone	UBERON:0003053	93.42	gold quality
cartilage tissue	UBERON:0002418	93.07	gold quality
tibia	UBERON:0000979	92.64	gold quality
globus pallidus	UBERON:0001875	92.58	gold quality
trigeminal ganglion	UBERON:0001675	92.16	gold quality
tendon of biceps brachii	UBERON:0008188	92.07	gold quality
cerebellar vermis	UBERON:0004720	92.06	gold quality
inferior vagus X ganglion	UBERON:0005363	91.88	gold quality
buccal mucosa cell	CL:0002336	91.12	gold quality
subthalamic nucleus	UBERON:0001906	90.67	gold quality
ganglionic eminence	UBERON:0004023	90.10	gold quality
spinal cord	UBERON:0002240	89.97	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	89.71	gold quality
medulla oblongata	UBERON:0001896	89.62	gold quality
oocyte	CL:0000023	89.06	gold quality
epithelium of mammary gland	UBERON:0003244	88.63	gold quality
mammary duct	UBERON:0001765	88.62	gold quality
upper arm skin	UBERON:0004263	88.62	gold quality
penis	UBERON:0000989	87.93	gold quality
pericardium	UBERON:0002407	87.83	gold quality
nipple	UBERON:0002030	87.70	gold quality
thoracic mammary gland	UBERON:0005200	87.66	gold quality
oviduct epithelium	UBERON:0004804	87.64	gold quality
mammary gland	UBERON:0001911	87.63	gold quality
secondary oocyte	CL:0000655	87.40	gold quality
pons	UBERON:0000988	87.33	gold quality
substantia nigra pars reticulata	UBERON:0001966	87.29	gold quality
superior vestibular nucleus	UBERON:0007227	87.25	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	4.68

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

124 targeting LDLRAD3, 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-190A-3P	100.00	80.35	5520
HSA-MIR-4510	100.00	66.60	2050
HSA-MIR-6127	100.00	66.76	2188
HSA-MIR-6129	100.00	66.46	2080
HSA-MIR-6130	100.00	66.69	2012
HSA-MIR-6133	100.00	66.48	2064
HSA-MIR-513A-5P	100.00	69.77	2465
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-4789-3P	99.99	70.75	2484
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-8068	99.98	73.85	2376
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-548AA	99.96	70.64	3753
HSA-MIR-548AP-3P	99.96	70.64	3753
HSA-MIR-548T-3P	99.96	70.64	3753
HSA-MIR-495-3P	99.96	72.81	4197
HSA-MIR-5688	99.96	73.23	4504
HSA-MIR-551B-5P	99.96	71.28	3493
HSA-MIR-128-3P	99.95	71.17	2484
HSA-MIR-216A-3P	99.95	71.19	2505
HSA-MIR-548J-3P	99.94	72.61	4881
HSA-MIR-539-5P	99.93	70.30	2855
HSA-MIR-145-5P	99.92	71.13	1836
HSA-MIR-5195-3P	99.92	70.92	1877
HSA-MIR-548E-5P	99.89	72.73	4486
HSA-MIR-9902	99.89	69.15	2250

Literature-anchored findings (GeneRIF, showing 11)

• LRAD3 that modulates amyloid precursor protein trafficking. (PMID:21795536)
• LRAD3 is a component of pathways that function effectively to modulate Itch and Nedd4 auto-ubiquitination and levels. (PMID:26854353)
• Data suggest that circular RNA circ-LDLRAD3 may be a biomarker in the diagnosis of pancreatic cancer. (PMID:29307994)
• Increased expression of circ-LDLRAD3 was indicative of a poor prognosis in patients with pancreatic cancer. Knockdown of circ-LDLRAD3 repressed the growth of pancreatic cancer in vitro and in vivo. miR-137-3p was identified as a direct target of circ-LDLRAD3. Upregulation of circ-LDLRAD3 could mitigate the inhibitory effect of miR-137-3p on the proliferation, migration and invasion of pancreatic cancer tissue and cells. (PMID:31521692)
• Circular RNA circ-LDLRAD3 serves as an oncogene to promote non-small cell lung cancer progression by upregulating SLC1A5 through sponging miR-137. (PMID:32658600)
• LDLRAD3 is a receptor for Venezuelan equine encephalitis virus. (PMID:33208938)
• Circ-LDLRAD3 Enhances Cell Growth, Migration, and Invasion and Inhibits Apoptosis by Regulating MiR-224-5p/NRP2 Axis in Gastric Cancer. (PMID:33389349)
• Structure of Venezuelan equine encephalitis virus in complex with the LDLRAD3 receptor. (PMID:34646020)
• Structure of Venezuelan equine encephalitis virus with its receptor LDLRAD3. (PMID:34646021)
• circ-LDLRAD3 Knockdown Reduces Cisplatin Chemoresistance and Inhibits the Development of Gastric Cancer with Cisplatin Resistance through miR-588 Enrichment-Mediated SOX5 Inhibition. (PMID:35975639)
• Circ-LDLRAD3/miR-655-3p/MAPK1 axis enhances cell migration and invasion in papillary thyroid carcinoma. (PMID:38430029)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Ldlrad3	ENSMUSG00000048058
rattus_norvegicus	Ldlrad3	ENSRNOG00000058157

Protein

Protein identifiers

Low-density lipoprotein receptor class A domain-containing protein 3 — Q86YD5 (reviewed: Q86YD5)

All UniProt accessions (2): E9PR86, Q86YD5

UniProt curated annotations — full annotation on UniProt →

Function. May influence APP processing, resulting in a decrease in sAPP-alpha production and increased amyloidogenic P3 peptide production. May regulate ITCH and NEDD4 E3 ligase activity and degradation. (Microbial infection) Acts as a receptor for Venezuelan equine encephalitis virus.

Subunit / interactions. Interacts with APP precursor C-terminus. Interacts directly with ITCH; this interaction promotes ITCH auto-ubiquitination leading to its degradation. Interacts directly with NEDD4; this interaction promotes NEDD4 auto-ubiquitination. Interacts directly with NEDD4L. (Microbial infection) Interacts (via domain LDL-receptor class A 1) with Venezuelan equine encephalitis virus/VEEV spike proteins E1 and E2.

Subcellular location. Cell membrane.

Tissue specificity. Expressed at high levels in brain, lung, skeletal muscle, and pancreas. Expressed at moderate levels in heart, placenta, and kidney but not detected in the liver.

Similarity. Belongs to the LDLR family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q86YD5-1	1	yes
Q86YD5-2	2

RefSeq proteins (3): NP_001291192, NP_001291193, NP_777562* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR002172	LDrepeatLR_classA_rpt	Repeat
IPR023415	LDLR_class-A_CS	Conserved_site
IPR036055	LDL_receptor-like_sf	Homologous_superfamily
IPR050685	LDLR	Family

Pfam: PF00057

UniProt features (43 total): mutagenesis site 12, disulfide bond 9, strand 3, domain 3, short sequence motif 2, topological domain 2, sequence conflict 2, helix 2, region of interest 2, signal peptide 1, chain 1, compositionally biased region 1, glycosylation site 1, splice variant 1, transmembrane region 1

Structure

Experimental structures (PDB)

3 structures.

PDB	Method	Resolution (Å)
7FFF	ELECTRON MICROSCOPY	3
7FFN	ELECTRON MICROSCOPY	3
7FFL	ELECTRON MICROSCOPY	3.1

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q86YD5-F1	61.68	0.06

Functional residue map

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

Disulfide bonds (9): 29–42, 37–55, 49–64, 71–84, 78–97, 91–106, 113–125, 120–138, 132–147

Glycosylation sites (1): 24

Mutagenesis-validated functional residues (12):

Position	Phenotype
33	loss of infection by venezuelan equine encephalitis virus.
36	loss of infection by venezuelan equine encephalitis virus.
44	loss of infection by venezuelan equine encephalitis virus.
47	complete loss of interaction with venezuelan equine encephalitis virus/veev spike proteins e1.
50	loss of infection by venezuelan equine encephalitis virus.
57	complete loss of interaction with venezuelan equine encephalitis virus/veev spike proteins e1.
57	loss of infection by venezuelan equine encephalitis virus.
257	does not affect interaction with itch; when associated with a-259. loss of interaction with itch; when associated with a
259	does not affect interaction with itch; when associated with a-257. loss of interaction with itch; when associated with a
276	does not affect interaction with itch; when associated with a-277 and a-278. loss of interaction with itch; when associa
277	does not affect interaction with itch; when associated with a-276 and a-278. loss of interaction with itch; when associa
278	does not affect interaction with itch; when associated with a-276 and a-277. loss of interaction with itch; when associa

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 145 (showing top): RNGTGGGC_UNKNOWN, GCANCTGNY_MYOD_Q6, AP4_Q6, GOBP_VESICLE_MEDIATED_TRANSPORT, CAGCTG_AP4_Q5, WEI_MYCN_TARGETS_WITH_E_BOX, GOBP_PROTEIN_MATURATION, CREIGHTON_ENDOCRINE_THERAPY_RESISTANCE_1, TGCTGAY_UNKNOWN, GOBP_REGULATION_OF_PROTEIN_MATURATION, AACTTT_UNKNOWN, GRYDER_PAX3FOXO1_ENHANCERS_IN_TADS, GOBP_IMPORT_INTO_CELL, GOBP_REGULATION_OF_PROTEOLYSIS, IVANOVA_HEMATOPOIESIS_EARLY_PROGENITOR

GO Biological Process (3): receptor-mediated endocytosis (GO:0006898), regulation of protein processing (GO:0070613), vesicle-mediated transport (GO:0016192)

GO Molecular Function (2): amyloid-beta binding (GO:0001540), protein binding (GO:0005515)

GO Cellular Component (3): plasma membrane (GO:0005886), endomembrane system (GO:0012505), membrane (GO:0016020)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	2
endocytosis	1
protein processing	1
regulation of proteolysis	1
regulation of protein maturation	1
transport	1
cellular process	1
peptide binding	1
binding	1
membrane	1
cell periphery	1
vacuole	1
plasma membrane	1

Protein interactions and networks

STRING

450 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
LDLRAD3	CLEC4G	Q6UXB4	557
LDLRAD3	APP	P05067	547
LDLRAD3	MXRA8	Q9BRK3	495
LDLRAD3	NEDD4	P46934	489
LDLRAD3	APOE	P02649	469
LDLRAD3	CDC50A	Q9NV96	452
LDLRAD3	PDE8A	O60658	447
LDLRAD3	A2M	P01023	429
LDLRAD3	SUMF2	Q8NBJ7	421
LDLRAD3	TTC17	Q96AE7	398
LDLRAD3	B4GALT7	Q9UBV7	394
LDLRAD3	PLAT	P00750	388
LDLRAD3	PLAU	P00749	384
LDLRAD3	ITCH	Q96J02	378
LDLRAD3	MYO3B	Q8WXR4	369

IntAct

3 interactions, top by confidence:

A	B	Type	Score
NEDD4	LDLRAD3	psi-mi:“MI:0407”(direct interaction)	0.440
WWP1	TP73	psi-mi:“MI:0914”(association)	0.350

BioGRID (18): LDLRAD3 (Affinity Capture-RNA), Itch (Reconstituted Complex), ITCH (Affinity Capture-Western), Nedd4 (Reconstituted Complex), Nedd4l (Reconstituted Complex), Dnm1 (Reconstituted Complex), Atp1a3 (Reconstituted Complex), LDLRAD3 (Affinity Capture-MS), LDLRAD3 (Affinity Capture-Western), LDLRAD3 (Reconstituted Complex), S (Reconstituted Complex), LDLRAD3 (Protein-peptide), LDLRAD3 (Affinity Capture-Western), LDLRAD3 (Affinity Capture-MS), LDLRAD3 (Affinity Capture-RNA)

ESM2 similar proteins: A2AR95, A4IHY6, B7ZWI3, D3ZF92, O15165, O43278, O75509, O88204, P98153, P98154, Q0VBF2, Q1L8G6, Q29RU0, Q4KMG9, Q566M8, Q5DTZ6, Q5HZW5, Q5R662, Q5R8E0, Q5RD34, Q5RF74, Q5VUB5, Q61003, Q68FU0, Q6AXS2, Q6NRX0, Q6UWW9, Q6ZPS6, Q6ZUJ8, Q7TQH7, Q86YD5, Q8BGN6, Q8BLD6, Q8BUJ9, Q8R182, Q8TEB7, Q8WUU8, Q91ZV2, Q91ZV3, Q96PD2

Diamond homologs: A2AR95, A2ARV4, A4IHY6, C0HL13, E9Q6D8, G3V928, O75074, O75197, O75581, O88204, O88307, O88572, P0DSP1, P13671, P35953, P56677, P61134, P61135, P86091, P98153, P98154, P98155, P98156, P98157, P98158, P98160, P98163, P98164, P98165, P98166, P98167, Q04833, Q06561, Q07954, Q0IIH7, Q14114, Q28832, Q29RU4, Q5HZW5, Q5R662

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	45
Likely benign	4
Benign	3

Top pathogenic / likely-pathogenic (0)

SpliceAI

2851 predictions. Top by Δscore:

Variant	Effect	Δscore
11:35944141:GCGG:G	donor_gain	1.0000
11:36001184:GTT:G	donor_gain	1.0000
11:36036098:GACA:G	acceptor_loss	1.0000
11:36036100:CA:C	acceptor_loss	1.0000
11:36036101:A:AG	acceptor_gain	1.0000
11:36036101:A:AT	acceptor_loss	1.0000
11:36036102:G:A	acceptor_loss	1.0000
11:36036102:G:GG	acceptor_gain	1.0000
11:36036102:GA:G	acceptor_gain	1.0000
11:36036102:GAGA:G	acceptor_gain	1.0000
11:36036245:GTGCC:G	donor_gain	1.0000
11:36036247:GCC:G	donor_gain	1.0000
11:36036250:G:GG	donor_gain	1.0000
11:36081648:T:A	acceptor_gain	1.0000
11:36081651:A:AG	acceptor_gain	1.0000
11:36081651:A:C	acceptor_loss	1.0000
11:36081652:G:GG	acceptor_gain	1.0000
11:36081652:GC:G	acceptor_gain	1.0000
11:36081652:GCC:G	acceptor_gain	1.0000
11:36081652:GCCA:G	acceptor_gain	1.0000
11:36081652:GCCAA:G	acceptor_gain	1.0000
11:36081774:CTGCA:C	donor_gain	1.0000
11:36081775:TGCA:T	donor_gain	1.0000
11:36081775:TGCAG:T	donor_loss	1.0000
11:36081776:GCA:G	donor_gain	1.0000
11:36081776:GCAG:G	donor_gain	1.0000
11:36081776:GCAGT:G	donor_loss	1.0000
11:36081777:CA:C	donor_gain	1.0000
11:36081777:CAGTA:C	donor_loss	1.0000
11:36081778:AGTAA:A	donor_loss	1.0000

AlphaMissense

2290 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
11:36098419:T:A	C138S	1.000
11:36098420:G:C	C138S	1.000
11:36227165:A:C	S179R	1.000
11:36227167:C:A	S179R	1.000
11:36227167:C:G	S179R	1.000
11:36036165:T:A	C37S	0.999
11:36036166:G:C	C37S	0.999
11:36036167:C:G	C37W	0.999
11:36036180:T:A	C42S	0.999
11:36036181:G:C	C42S	0.999
11:36036219:T:A	C55S	0.999
11:36036219:T:C	C55R	0.999
11:36036220:G:A	C55Y	0.999
11:36036220:G:C	C55S	0.999
11:36036221:C:G	C55W	0.999
11:36081692:G:A	C78Y	0.999
11:36081693:T:G	C78W	0.999
11:36081730:T:A	C91S	0.999
11:36081731:G:C	C91S	0.999
11:36081748:T:A	C97S	0.999
11:36081748:T:C	C97R	0.999
11:36081749:G:A	C97Y	0.999
11:36081749:G:C	C97S	0.999
11:36081750:T:G	C97W	0.999
11:36081763:G:T	D102Y	0.999
11:36098365:T:A	C120S	0.999
11:36098365:T:C	C120R	0.999
11:36098366:G:A	C120Y	0.999
11:36098366:G:C	C120S	0.999
11:36098367:C:G	C120W	0.999

dbSNP variants (sampled 300 via entrez): RS1000004421 (11:36050820 C>T), RS1000033728 (11:36210068 A>G), RS1000035018 (11:36176151 T>A), RS1000041395 (11:36201966 T>C), RS1000047372 (11:36127145 A>G), RS1000059235 (11:36169336 A>G), RS1000073133 (11:36075290 C>G), RS1000095583 (11:35958273 G>A,T), RS1000098767 (11:36050455 G>A), RS1000102317 (11:36114756 G>A), RS1000114351 (11:36139928 G>C,T), RS1000125849 (11:35963539 T>G), RS1000145927 (11:36015514 G>A), RS1000156399 (11:36056831 A>T), RS1000176941 (11:36210622 G>C)

Disease associations

OMIM: gene MIM:617986 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

4 associations (top):

Study	Trait	p-value
GCST010396_73	Gut microbiota (bacterial taxa, hurdle binary method)	9.000000e-06
GCST90002388_533	Lymphocyte count	2.000000e-17
GCST90002389_461	Lymphocyte percentage of white cells	2.000000e-12
GCST90002399_61	Neutrophil percentage of white cells	1.000000e-09

EFO canonical traits (4, from GWAS)

EFO ID	Trait name
EFO:0007874	gut microbiome measurement
EFO:0004587	lymphocyte count
EFO:0007993	lymphocyte percentage of leukocytes
EFO:0007990	neutrophil percentage of leukocytes

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, decreases expression	4
Estradiol	increases expression, affects cotreatment, decreases expression	3
trichostatin A	affects cotreatment, decreases expression	2
Air Pollutants	decreases expression, increases abundance	2
Phenylmercuric Acetate	affects cotreatment, decreases expression	2
Tobacco Smoke Pollution	decreases expression	2
Tretinoin	decreases expression	2
Cadmium Chloride	decreases expression, increases abundance	2
Particulate Matter	decreases expression, increases abundance	2
aristolochic acid I	decreases expression	1
sodium arsenite	decreases expression	1
potassium chromate(VI)	affects cotreatment, decreases expression	1
S-(1,2-dichlorovinyl)cysteine	decreases reaction, increases expression	1
epigallocatechin gallate	affects cotreatment, decreases expression	1
di-n-butylphosphoric acid	affects expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
abrine	decreases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
gardiquimod	increases expression, decreases reaction	1
Sunitinib	increases expression	1
Benzo(a)pyrene	increases methylation	1
Cadmium	decreases expression, increases abundance	1
Cisplatin	decreases expression	1
Lipopolysaccharides	increases expression, decreases reaction	1
Nicotine	increases splicing	1
Silicon Dioxide	increases expression	1
Sodium Dodecyl Sulfate	decreases expression	1
Dihydrotestosterone	increases expression	1
Dronabinol	increases expression	1
Thiram	decreases expression	1

Cellosaurus cell lines

1 cell lines: 1 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_D7GT	Ubigene HEK293T LDLRAD3 KO	Transformed cell line	Female

Clinical trials (associated diseases)

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