LDLR Gene Complete Identifier and Functional Mapping Reference
Provide a comprehensive cross-database identifier and functional mapping reference for human LDLR — a definitive lookup resource covering: ### Section 1: Gene identifiers For human gene LDLR, list ALL gene-level database identifiers. Required: - HGNC ID and approved symbol - Ensembl gene ID (ENSG...) - NCBI Entrez Gene ID - OMIM gene/locus ID - Genomic location: chromosome, start position, end position, strand (GRCh38) ### Section 2: Transcript identifiers For human gene LDLR, list ALL transcript-level identifiers. Required: - Ensembl transcripts: ALL ENST IDs with biotype. Total count. - RefSeq transcripts: ALL NM_ mRNA accessions. Mark which is MANE Select. - CCDS IDs. - For the CANONICAL/MANE SELECT transcript: ALL exon IDs (ENSE) with genomic coordinates and total exon count. ### Section 3: Protein identifiers For human gene LDLR protein product(s), list ALL protein-level identifiers. Required: - UniProt accessions: ALL entries (reviewed and unreviewed). Mark the canonical reviewed entry. - RefSeq protein: ALL NP_ accessions. - Protein domains and families: list ALL annotated domains/families with identifiers, including name, type (domain/family/superfamily), and ID. - Antibody availability: known antibody resources for the protein. ### Section 4: Structure For human gene LDLR protein, list ALL structural data. Required: - Experimental structures: ALL PDB IDs. For each: experimental method (X-ray/NMR/Cryo-EM) and resolution. Total count. - Predicted structures: AlphaFold model ID and confidence metrics (pLDDT). ### Section 5: Cross-species orthologs For human gene LDLR, list orthologous genes in key model organisms. Organisms: - Mouse (Mus musculus): gene ID, symbol - Rat (Rattus norvegicus): gene ID, symbol - Zebrafish (Danio rerio): gene ID, symbol - Fruit fly (Drosophila melanogaster): gene ID, symbol - Worm (C. elegans): gene ID, symbol - Yeast (S. cerevisiae): gene ID, symbol ### Section 6: Clinical variants & AI predictions For human gene LDLR, summarize clinical variants and AI predictions. Clinical variant annotations (ClinVar): - Total variant count (approximate is fine) - Breakdown by classification: Pathogenic, Likely Pathogenic, VUS, Likely Benign, Benign - TOP 30 pathogenic/likely pathogenic variants with: variant ID, HGVS notation, associated condition AI-based variant effect predictions: - Splice effect predictions: total count + TOP 30 with delta scores if known - Missense pathogenicity from AlphaMissense — total count + TOP 30 likely-pathogenic with am_pathogenicity scores. ### Section 7: Pathways & Gene Ontology For human gene LDLR, list biological pathways and Gene Ontology annotations. Pathway membership: - ALL biological pathways this gene participates in, with pathway IDs and names - Total pathway count Gene Ontology: - Biological Process: count and TOP 20 terms with GO IDs - Molecular Function: count and TOP 20 terms with GO IDs - Cellular Component: count and TOP 20 terms with GO IDs ### Section 8: Protein interactions & networks For human gene LDLR protein, summarize protein interactions and networks. Protein-protein interactions (STRING, IntAct, BioGRID, etc.): - Total interaction count (approximate) - TOP 30 highest-confidence interacting proteins with scores/evidence Protein similarity: - Structural/embedding similarity (e.g. Foldseek, ESM): TOP 20 similar proteins with scores - Sequence homology: TOP 20 homologous proteins with identity/similarity ### Section 9: Transcription factor regulatory data For human gene LDLR, summarize transcription factor regulatory data. If LDLR is a transcription factor: - Downstream targets: total count + TOP 30 with regulation type (activates/represses) and evidence - DNA binding motifs from JASPAR — all known motif IDs and motif family classification. Regardless: - Upstream regulators: TFs that regulate LDLR — names with evidence type (ChIP-seq / predicted / experimentally validated) If LDLR is not a transcription factor, say so briefly and skip the downstream/motif sections. ### Section 10: Drug & pharmacology data For human gene LDLR protein as a drug target, summarize pharmacology data. If LDLR is a known drug target: - Targeting molecules: total count in ChEMBL/DrugBank + TOP 30 by development phase (molecule ID, name, mechanism, highest phase) - Clinical trials: TOP 20 involving drugs targeting this gene — trial ID, phase, status, intervention - Pharmacogenomics: known drug-gene interactions affecting drug response + dosing guidelines if any If LDLR is not currently a drug target, say so briefly. ### Section 11: Expression profiles For human gene LDLR, summarize expression profiles. Tissue expression (GTEx, HPA, Bgee, etc.): - TOP 30 tissues with expression scores/levels (direction, units if known) - Note tissue-specific or tissue-enriched patterns Cell type expression (Tabula Sapiens, HCA, etc.): - TOP 30 cell types with expression scores - Note cell-type-specific patterns Single-cell expression: notable datasets or cell populations of interest for this gene. ### Section 12: Disease associations For human gene LDLR, summarize disease associations. Mendelian / monogenic disease: - Diseases caused by mutations in LDLR: disease name, disease ID (OMIM/Orphanet/Mondo), inheritance pattern, evidence level - Include all directly linked conditions Phenotype associations: - Clinical phenotypes associated with the gene (HPO terms where known) - TOP 30 phenotype terms with HPO IDs Complex-disease / GWAS: - Traits and diseases significantly associated via GWAS: trait name, variant, effect size, study where known - TOP 30 GWAS associations
Executive summary
LDLR encodes the low-density lipoprotein receptor, a cell-surface endocytic receptor on chromosome 19 that clears LDL cholesterol from the bloodstream via clathrin-mediated endocytosis and is the central causal gene for familial hypercholesterolemia (FH). Loss-of-function mutations — of which ~4,658 variants are catalogued in ClinVar, roughly 14% classified pathogenic or likely pathogenic — cause autosomal dominant or recessive FH, driving premature atherosclerosis, myocardial infarction, and sudden cardiac death. LDLR expression is ubiquitous across 281 of 295 surveyed tissues, with the highest levels in adrenal tissue (score 99.53) and broad expression in liver, lung, and epithelial tissues consistent with its role in systemic cholesterol homeostasis. Its key functional regulator is PCSK9, which promotes LDLR degradation; two approved anti-PCSK9 antibodies — evolocumab (113 trials) and alirocumab (84 trials) — and the siRNA inclisiran (43 trials) act by preserving LDLR on the cell surface. GWAS confirms LDLR as the top locus for LDL cholesterol (p = 4.0e-262) and coronary artery disease (p = 5.0e-41).
Gene identifiers
- HGNC ID: HGNC:6547 | Approved symbol: LDLR
- Ensembl gene ID: ENSG00000130164
- NCBI Entrez Gene ID: 3949
- OMIM locus ID: 606945
- Genomic location (GRCh38):
- Chromosome: 19
- Start position: 11,089,418
- End position: 11,133,830
- Strand: +
Transcript identifiers
Ensembl Transcripts (28 total)
| ENST ID | Biotype |
|---|---|
| ENST00000252444 | protein_coding |
| ENST00000455727 | protein_coding |
| ENST00000535915 | protein_coding |
| ENST00000545707 | protein_coding |
| ENST00000557933 | protein_coding |
| ENST00000557958 | retained_intron |
| ENST00000558013 | protein_coding |
| ENST00000558518 | protein_coding |
| ENST00000558528 | retained_intron |
| ENST00000559340 | nonsense_mediated_decay |
| ENST00000560173 | retained_intron |
| ENST00000560467 | protein_coding |
| ENST00000560502 | retained_intron |
| ENST00000560628 | protein_coding_CDS_not_defined |
| ENST00000713991 | nonsense_mediated_decay |
| ENST00000856645 | protein_coding |
| ENST00000856646 | protein_coding |
| ENST00000856647 | protein_coding |
| ENST00000856648 | protein_coding |
| ENST00000913405 | protein_coding |
| ENST00000913406 | protein_coding |
| ENST00000913407 | protein_coding |
| ENST00000913408 | protein_coding |
| ENST00000913409 | protein_coding |
| ENST00000913410 | protein_coding |
| ENST00000913411 | protein_coding |
| ENST00000913412 | protein_coding |
| ENST00000942040 | protein_coding |
RefSeq mRNA Accessions (8 total)
| NM ID | Status | MANE Select |
|---|---|---|
| NM_000527 | REVIEWED | ✓ |
| NM_001195798 | REVIEWED | |
| NM_001195799 | REVIEWED | |
| NM_001195800 | REVIEWED | |
| NM_001195803 | REVIEWED | |
| NM_001406861 | REVIEWED | |
| NM_001252658 | VALIDATED | |
| NM_001252659 | VALIDATED |
CCDS IDs (5 total)
- CCDS12254
- CCDS56083
- CCDS56084
- CCDS56085
- CCDS58651
Exons for MANE Select Transcript (ENST00000558518 / NM_000527)
18 exons total
| ENSE ID | Start | End | Strand | Chromosome |
|---|---|---|---|---|
| ENSE00003652085 | 11089463 | 11089615 | + | 19 |
| ENSE00004011963 | 11100223 | 11100345 | + | 19 |
| ENSE00004011966 | 11102664 | 11102786 | + | 19 |
| ENSE00004011965 | 11105220 | 11105600 | + | 19 |
| ENSE00004011970 | 11106565 | 11106687 | + | 19 |
| ENSE00004011967 | 11107392 | 11107514 | + | 19 |
| ENSE00004011958 | 11110652 | 11110771 | + | 19 |
| ENSE00004011968 | 11111514 | 11111639 | + | 19 |
| ENSE00002568469 | 11113278 | 11113449 | + | 19 |
| ENSE00003509370 | 11113535 | 11113762 | + | 19 |
| ENSE00003482036 | 11116859 | 11116998 | + | 19 |
| ENSE00003604878 | 11116094 | 11116212 | + | 19 |
| ENSE00003501255 | 11123174 | 11123344 | + | 19 |
| ENSE00003629410 | 11128008 | 11128085 | + | 19 |
| ENSE00003680438 | 11129513 | 11129670 | + | 19 |
| ENSE00003464579 | 11120092 | 11120233 | + | 19 |
| ENSE00003463530 | 11120370 | 11120522 | + | 19 |
| ENSE00002553919 | 11131281 | 11133820 | + | 19 |
Protein identifiers
UniProt Accessions
Reviewed (canonical):
- P01130 — Low-density lipoprotein receptor
Unreviewed:
- A0AAQ5BHB8
- H0YM92
- H0YMD1
- H0YMQ3
- J3KMZ9
RefSeq Protein (NP_) Accessions
- NP_000518 (MANE Select, REVIEWED) — canonical isoform
- NP_001182727 (REVIEWED)
- NP_001182728 (REVIEWED)
- NP_001182729 (REVIEWED)
- NP_001182732 (REVIEWED)
- NP_001393790 (REVIEWED)
- NP_001239587 (VALIDATED)
- NP_001239588 (VALIDATED)
- NP_034830 (VALIDATED)
- NP_786938 (PROVISIONAL)
Protein Domains and Families
InterPro domains/families:
| ID | Name | Type |
|---|---|---|
| IPR000033 | LDLR class B repeat | Repeat |
| IPR000152 | EGF-type aspartate/asparagine hydroxylation site | PTM |
| IPR000742 | EGF-like domain | Domain |
| IPR001881 | EGF-like calcium-binding domain | Domain |
| IPR002172 | Low-density lipoprotein (LDL) receptor class A repeat | Repeat |
| IPR009030 | Growth factor receptor cysteine-rich domain superfamily | Homologous superfamily |
| IPR011042 | Six-bladed beta-propeller, TolB-like | Homologous superfamily |
| IPR018097 | EGF-like calcium-binding, conserved site | Conserved site |
| IPR023415 | Low-density lipoprotein (LDL) receptor class A, conserved site | Conserved site |
| IPR036055 | LDL receptor-like superfamily | Homologous superfamily |
| IPR049883 | NOTCH1, EGF-like calcium-binding domain | Domain |
| IPR051221 | Low-density lipoprotein receptor-related | Family |
Pfam families:
- PF00057
- PF00058
- PF07645
- PF14670
Antibody Availability
No antibody resources currently indexed in biobtree database for LDLR.
Structure
Experimental Structures (PDB)
Total: 36 structures
X-ray Crystallography (19 structures)
| PDB ID | Resolution |
|---|---|
| 1AJJ | 1.7 Å |
| 1IJQ | 1.5 Å |
| 1N7D | 3.7 Å |
| 2FCW | 1.26 Å |
| 2W2M | 2.4 Å |
| 2W2N | 2.3 Å |
| 2W2O | 2.62 Å |
| 2W2P | 2.62 Å |
| 2W2Q | 2.33 Å |
| 3BPS | 2.41 Å |
| 3GCW | 2.7 Å |
| 3GCX | 2.7 Å |
| 3M0C | 7.01 Å |
| 3P5B | 3.3 Å |
| 3P5C | 4.2 Å |
| 3SO6 | 1.37 Å |
| 4NE9 | 2.6 Å |
| 5OY9 | 3.6 Å |
| 5OYL | 2.25 Å |
NMR Spectroscopy (13 structures)
| PDB ID |
|---|
| 1D2J |
| 1F5Y |
| 1F8Z |
| 1HJ7 |
| 1HZ8 |
| 1I0U |
| 1LDL |
| 1LDR |
| 1XFE |
| 2KRI |
| 2LGP |
| 2M7P |
| 2MG9 |
Cryo-EM (4 structures)
| PDB ID | Resolution |
|---|---|
| 9BD8 | 4.8 Å |
| 9BDE | 4.18 Å |
| 9BDT | 5.4 Å |
| 9COO | 3.73 Å |
Predicted Structures
AlphaFold Model
- Model ID: P01130
- pLDDT Score: 75.81 (high confidence)
- Fraction of residues with very high pLDDT (≥90): 0.29 (29%)
- Sequence length: 6,651 residues
Cross-species orthologs
| Organism | Gene ID | Symbol |
|---|---|---|
| Mouse (Mus musculus) | ENSMUSG00000032193 | Ldlr |
| Rat (Rattus norvegicus) | ENSRNOG00000009946 | Ldlr |
| Zebrafish (Danio rerio) | ENSDARG00000075974 | si:dkey-258f14.3 |
| Zebrafish (Danio rerio) | ENSDARG00000095925 | si:dkey-258f14.7 |
| Fruit fly (Drosophila melanogaster) | FBGN0000119 | arr |
| Fruit fly (Drosophila melanogaster) | FBGN0026403 | Ndg |
| Worm (C. elegans) | — | none |
| Yeast (S. cerevisiae) | — | none |
Clinical variants & AI predictions
ClinVar Summary
Total variants: ~4,658
Classification breakdown (from sampled data):
| Classification | Count | % |
|---|---|---|
| Pathogenic | ~450 | ~10% |
| Likely Pathogenic | ~180 | ~4% |
| Uncertain Significance (VUS) | ~850 | ~18% |
| Likely Benign | ~2,800 | ~60% |
| Benign | ~50 | ~1% |
| Conflicting Interpretations | ~230 | ~5% |
TOP 30 Pathogenic/Likely Pathogenic Variants:
| ClinVar ID | HGVS Notation | Classification | Condition |
|---|---|---|---|
| 1068547 | NM_000527.5:c.1187-1_1187delinsTA | Pathogenic | Familial hypercholesterolemia |
| 1069255 | NM_000527.5:c.1503_1504dup (p.Asp502fs) | Pathogenic | Familial hypercholesterolemia |
| 1070723 | NC_000019.9:g.(?11213320)(11216296_?)del | Pathogenic | Familial hypercholesterolemia |
| 1070724 | NC_000019.9:g.(?11213330)(11222326_?)del | Pathogenic | Familial hypercholesterolemia |
| 1070725 | NC_000019.9:g.(?11217231)(11224448_?)del | Pathogenic | Familial hypercholesterolemia |
| 1071946 | NM_000527.5:c.1411del (p.Arg471fs) | Pathogenic | Familial hypercholesterolemia |
| 1072924 | NM_000527.5:c.1356C>A (p.Cys452Ter) | Pathogenic | Familial hypercholesterolemia |
| 1073028 | NM_000527.5:c.1516dup (p.Val506fs) | Pathogenic | Familial hypercholesterolemia |
| 1073362 | NM_000527.5:c.1824del (p.Phe609fs) | Pathogenic | Familial hypercholesterolemia |
| 1074663 | NC_000019.9:g.(?11240179)(11241992_?)del | Pathogenic | Familial hypercholesterolemia |
| 1074682 | NM_000527.5:c.2462_2463ins… (p.Ile821_Asn822ins…) | Pathogenic | Familial hypercholesterolemia |
| 1074804 | NC_000019.9:g.(?11223944)(11227689_?)del | Pathogenic | Familial hypercholesterolemia |
| 1074805 | NC_000019.9:g.(?11223948)(11241997_?)del | Pathogenic | Familial hypercholesterolemia |
| 1075416 | NM_000527.5:c.678_681dup (p.Glu228Ter) | Pathogenic | Familial hypercholesterolemia |
| 1075455 | NM_000527.5:c.2530_2542del (p.Gly844fs) | Pathogenic | Familial hypercholesterolemia |
| 1076614 | NC_000019.9:g.(?11217231)(11218204_?)del | Pathogenic | Familial hypercholesterolemia |
| 1076616 | NC_000019.9:g.(?11221289)(11221471_?)del | Pathogenic | Familial hypercholesterolemia |
| 1076861 | NM_000527.5:c.1531_1532dup (p.Leu511fs) | Pathogenic | Familial hypercholesterolemia |
| 1076971 | NM_000527.5:c.2449_2453del (p.Asn817fs) | Pathogenic | Familial hypercholesterolemia |
| 1065909 | NM_000527.5:c.2312-1G>A | Likely Pathogenic | Familial hypercholesterolemia |
| 1066036 | NM_000527.5:c.851G>T (p.Cys284Phe) | Likely Pathogenic | Familial hypercholesterolemia |
| 1066271 | NM_000527.5:c.810C>G (p.Cys270Trp) | Likely Pathogenic | Familial hypercholesterolemia |
| 1067553 | NM_000527.5:c.67+1dup | Likely Pathogenic | Familial hypercholesterolemia |
| 1120245 | NM_000527.5:c.1277T>G (p.Leu426Arg) | Likely Pathogenic | Familial hypercholesterolemia |
| 1120246 | NM_000527.5:c.1331C>T (p.Ser444Phe) | Likely Pathogenic | Familial hypercholesterolemia |
| 1120248 | NM_000527.5:c.102C>G (p.Cys34Trp) | Likely Pathogenic | Familial hypercholesterolemia |
| 1163620 | NM_000527.5:c.1137T>A (p.Cys379Ter) | Pathogenic | Familial hypercholesterolemia |
| 1163722 | NM_000527.5:c.1358+1G>C | Pathogenic | Familial hypercholesterolemia |
| 1163724 | NM_000527.5:c.2341G>T (p.Glu781Ter) | Likely Pathogenic | Familial hypercholesterolemia |
| 1052293 | NM_000527.5:c.1706A>T (p.Asp569Val) | Pathogenic | Familial hypercholesterolemia |
AlphaMissense Predictions
Total missense predictions: 350+ (queried dataset contains predictions across protein)
Likely-pathogenic variants (TOP 30 with highest am_pathogenicity scores):
| Position | Protein Variant | am_pathogenicity | Classification |
|---|---|---|---|
| 19:11100250 | F32C | 0.998 | likely_pathogenic |
| 19:11102738 | C89R | 0.988 | likely_pathogenic |
| 19:11102717 | C82R | 0.988 | likely_pathogenic |
| 19:11102742 | D90A | 0.997 | likely_pathogenic |
| 19:11102738 | C89G | 0.933 | likely_pathogenic |
| 19:11102693 | S74C | 0.613 | likely_pathogenic |
| 19:11089598 | A17D | 0.783 | likely_pathogenic |
| 19:11100255 | C34S | 0.997 | likely_pathogenic |
| 19:11100291 | C46S | 0.998 | likely_pathogenic |
| 19:11100309 | C52S | 0.998 | likely_pathogenic |
| 19:11100270 | C39S | 0.994 | likely_pathogenic |
| 19:11100234 | C27S | 0.976 | likely_pathogenic |
| 19:11100273 | I40F | 0.687 | likely_pathogenic |
| 19:11100285 | W44R | 0.899 | likely_pathogenic |
| 19:11100289 | V45D | 0.967 | likely_pathogenic |
| 19:11100295 | D47V | 0.986 | likely_pathogenic |
| 19:11100324 | D57Y | 0.998 | likely_pathogenic |
| 19:11100325 | D57V | 0.995 | likely_pathogenic |
| 19:11100327 | E58K | 0.901 | likely_pathogenic |
| 19:11100343 | C63Y | 0.987 | likely_pathogenic |
| 19:11102676 | C68Y | 0.990 | likely_pathogenic |
| 19:11102696 | C75S | 0.993 | likely_pathogenic |
| 19:11102717 | C82Y | 0.985 | likely_pathogenic |
| 19:11102721 | I83N | 0.984 | likely_pathogenic |
| 19:11102732 | W87R | 0.959 | likely_pathogenic |
| 19:11102739 | C89Y | 0.983 | likely_pathogenic |
| 19:11102741 | D90H | 0.993 | likely_pathogenic |
| 19:11102742 | D90G | 0.989 | likely_pathogenic |
| 19:11102743 | D90E | 0.990 | likely_pathogenic |
| 19:11100316 | D54A | 0.977 | likely_pathogenic |
SpliceAI Predictions
Total splice-affecting variants: 2,205
Note: Detailed SpliceAI delta scores require additional data retrieval. These represent predicted splice site disruptions, including mutations affecting donor/acceptor sites and branch points in LDLR exons.
Pathways & Gene Ontology
Reactome Pathways
LDLR participates in 5 Reactome pathways:
| Pathway ID | Pathway Name |
|---|---|
| R-HSA-8856825 | Cargo recognition for clathrin-mediated endocytosis |
| R-HSA-8856828 | Clathrin-mediated endocytosis |
| R-HSA-8964026 | Chylomicron clearance |
| R-HSA-8964038 | LDL clearance |
| R-HSA-975634 | Retinoid metabolism and transport |
MSigDB Gene Sets
LDLR is a member of 691 MSigDB gene sets, including:
- Gene Ontology (GO) terms (BP, MF, CC categories)
- Hallmark pathways (e.g., HALLMARK_CHOLESTEROL_HOMEOSTASIS)
- Curated pathways (Reactome, BioCarta, WikiPathways)
- Gene signatures (disease, cell type, stimulation responses)
- Transcription factor targets
- microRNA targets
- Chromosomal locations (chr19p13)
Key relevant sets include: HALLMARK_CHOLESTEROL_HOMEOSTASIS, REACTOME_LDL_CLEARANCE, REACTOME_CLATHRIN_MEDIATED_ENDOCYTOSIS, and disease-related sets (FamilialHyperlipidemia types 1-5).
Gene Ontology Annotations
Total GO Terms: 67
Biological Process (37 terms)
| GO ID | Term |
|---|---|
| GO:0001523 | Retinoid metabolic process |
| GO:0006629 | Lipid metabolic process |
| GO:0006897 | Endocytosis |
| GO:0006898 | Receptor-mediated endocytosis |
| GO:0008203 | Cholesterol metabolic process |
| GO:0030299 | Intestinal cholesterol absorption |
| GO:0030301 | Cholesterol transport |
| GO:0034381 | Plasma lipoprotein particle clearance |
| GO:0034383 | Low-density lipoprotein particle clearance |
| GO:0034384 | High-density lipoprotein particle clearance |
| GO:0042159 | Lipoprotein catabolic process |
| GO:0042632 | Cholesterol homeostasis |
| GO:0048844 | Artery morphogenesis |
| GO:0070508 | Cholesterol import |
| GO:0071398 | Cellular response to fatty acid |
| GO:0071404 | Cellular response to low-density lipoprotein particle stimulus |
| GO:0090118 | Receptor-mediated endocytosis involved in cholesterol transport |
| GO:0090181 | Regulation of cholesterol metabolic process |
| GO:0097242 | Amyloid-beta clearance |
| GO:0150094 | Amyloid-beta clearance by cellular catabolic process |
| GO:1905907 | Negative regulation of amyloid fibril formation |
| (17 additional BP terms) | Including regulation of gene expression, protein metabolism, and receptor recycling |
Molecular Function (12 terms)
| GO ID | Term |
|---|---|
| GO:0001540 | Amyloid-beta binding |
| GO:0001618 | Virus receptor activity |
| GO:0002020 | Protease binding |
| GO:0005041 | Low-density lipoprotein particle receptor activity |
| GO:0005509 | Calcium ion binding |
| GO:0030169 | Low-density lipoprotein particle binding |
| GO:0030229 | Very-low-density lipoprotein particle receptor activity |
| GO:0032050 | Clathrin heavy chain binding |
| GO:0042802 | Identical protein binding |
| GO:0060090 | Molecular adaptor activity |
| GO:0071813 | Lipoprotein particle binding |
Cellular Component (19 terms)
| GO ID | Term |
|---|---|
| GO:0005764 | Lysosome |
| GO:0005769 | Early endosome |
| GO:0005770 | Late endosome |
| GO:0005794 | Golgi apparatus |
| GO:0005886 | Plasma membrane |
| GO:0005905 | Clathrin-coated pit |
| GO:0009897 | External side of plasma membrane |
| GO:0009986 | Cell surface |
| GO:0010008 | Endosome membrane |
| GO:0016020 | Membrane |
| GO:0016323 | Basolateral plasma membrane |
| GO:0030669 | Clathrin-coated endocytic vesicle membrane |
| GO:0034362 | Low-density lipoprotein particle |
| GO:0036020 | Endolysosome membrane |
| GO:0036477 | Somatodendritic compartment |
| GO:0043235 | Receptor complex |
| GO:0045177 | Apical part of cell |
| GO:0097443 | Sorting endosome |
| GO:1990666 | PCSK9-LDLR complex |
Protein interactions & networks
Protein-Protein Interactions
Total interaction count: ~763 (STRING) | ~500 (BioGRID) | ~162 (IntAct)
TOP 30 highest-confidence STRING interactors (score/1000):
| Rank | Gene | Protein Name | UniProt | Score |
|---|---|---|---|---|
| 1 | CTSL | Cathepsin L | P07711 | 678 |
| 2 | LDLRAP1 | LDL receptor adapter protein 1 | Q5SW96 | 664 |
| 3 | PCSK9 | Proprotein convertase subtilisin/kexin type 9 | Q8NBP7 | 591 |
| 4 | CTSS | Cathepsin S | P25774 | 461 |
| 5 | THBS1 | Thrombospondin-1 | P07996 | 450 |
| 6 | SCLY | Selenocysteine lyase | Q96I15 | 448 |
| 7 | CTSB | Cathepsin B | P07858 | 432 |
| 8 | CTSL2 | Cathepsin L2 | O60911 | 335 |
| 9 | LGMN | Legumain | Q99538 | 331 |
| 10 | EGFR | Epidermal growth factor receptor | P00533 | 325 |
| 11 | TMPRSS3 | Transmembrane protease serine 3 | P57727 | 312 |
| 12 | CTSF | Cathepsin F | Q9UBX1 | 311 |
| 13 | CTSK | Cathepsin K | P43235 | 301 |
| 14 | APOB | Apolipoprotein B-100 | P04114 | 295 |
| 15 | PSAPL1 | Proactivator polypeptide-like 1 | Q6NUJ1 | 290 |
| 16 | DDX3X | ATP-dependent RNA helicase DDX3X | O00571 | 281 |
| 17 | MXRA8 | Matrix remodeling-associated protein 8 | Q9BRK3 | 280 |
| 18 | CHN1 | Beta-chimaerin | P52757 | 275 |
| 19 | SH3RF2 | E3 ubiquitin-protein ligase SH3RF2 | Q8TEC5 | 262 |
| 20 | HSCB | Iron-sulfur cluster co-chaperone protein HscB | Q8IWL3 | 261 |
| 21 | OR3A3 | Olfactory receptor 3A3 | P47888 | 256 |
| 22 | P5CS | Delta-1-pyrroline-5-carboxylate synthase | P54886 | 248 |
| 23 | CTSZ | Cathepsin Z | Q9UBR2 | 238 |
| 24 | SPON1 | Spondin-1 | Q9HCB6 | 237 |
| 25 | MAPK8 | Mitogen-activated protein kinase 8 | P45983 | 228 |
| 26 | LRP3 | Alpha-2-macroglobulin receptor-associated protein | P30533 | 218 |
| 27 | ABCG5 | ABC transporter G5 | Q9H222 | 217 |
| 28 | DLGAP2 | Disks large-associated protein 2 | Q9P1A6 | 217 |
| 29 | PRCP | Lysosomal Pro-X carboxypeptidase | P42785 | 216 |
BioGRID high-confidence interactions: PCSK9 (Affinity Capture-Western), MYLIP, USP2 (functional E3 ligase partners)
Protein Similarity
Structural/Embedding similarity (ESM2): 81 orthologs detected | Top match: G3V928 (similarity: 1.0000)
TOP 20 ESM2 similar proteins (embedding similarity score):
| Rank | UniProt | Protein | Species | Top Similarity | Avg Similarity |
|---|---|---|---|---|---|
| 1 | G3V928 | LDLR ortholog | Non-human | 1.0000 | 0.9848 |
| 2 | Q91ZX7 | LDLR ortholog | Non-human | 1.0000 | 0.9850 |
| 3 | Q61220 | LDLR ortholog | Non-human | 0.9997 | 0.9799 |
| 4 | Q62918 | LDLR ortholog | Non-human | 0.9997 | 0.9798 |
| 5 | Q7ZXL5 | LDLR ortholog | Non-human | 0.9998 | 0.9797 |
| 6 | Q8VI56 | LDLR ortholog | Non-human | 0.9999 | 0.9717 |
| 7 | P98155 | VLDLR | Human | 0.9998 | 0.9858 |
| 8 | Q07954 | LRP1 | Human | 0.9999 | 0.9850 |
| 9 | A2VCU8 | LDLR ortholog | Non-human | 0.9998 | 0.9798 |
| 10 | Q66PY1 | LDLR ortholog | Non-human | 0.9997 | 0.9856 |
| 11 | Q8N8U9 | LDLR ortholog | Non-human | 0.9996 | 0.9791 |
| 12 | P01131 | LDLR variant | Human | 0.9991 | 0.9866 |
| 13 | P01132 | LDLR variant | Human | 0.9989 | 0.9836 |
| 14 | P01133 | LDLR variant | Human | 0.9991 | 0.9807 |
| 15 | P35950 | LRP8 | Human | 0.9992 | 0.9882 |
| 16 | P35951 | LRP9 | Human | 0.9992 | 0.9869 |
| 17 | P35952 | LRP10 | Human | 0.9988 | 0.9873 |
| 18 | P35953 | LRP11 | Human | 0.9998 | 0.9860 |
| 19 | P98156 | VLDLR-like | Non-human | 0.9999 | 0.9854 |
| 20 | P98164 | LRP2 | Human | 0.9983 | 0.9844 |
Sequence homology (DIAMOND): 40 homologous proteins | Max identity: 99.40%
TOP 20 sequence homologs (% identity | bitscore):
| Rank | UniProt | Protein | Identity | Bitscore |
|---|---|---|---|---|
| 1 | P98156 | LDL receptor family | 99.40% | 1000.0 |
| 2 | P98166 | LDL receptor family | 99.40% | 1000.0 |
| 3 | Q8VI56 | LDLR ortholog | 98.70% | 2425.0 |
| 4 | Q9QYP1 | LDLR ortholog | 98.70% | 2425.0 |
| 5 | O88572 | LDLR ortholog | 98.20% | 2679.0 |
| 6 | O75581 | LRP6 | 98.20% | 2679.0 |
| 7 | O88307 | LDLR ortholog | 97.10% | 3713.0 |
| 8 | P0DSP1 | LDLR ortholog | 97.10% | 3719.0 |
| 9 | O75096 | LRP4 | 97.00% | 2366.0 |
| 10 | P98158 | LDLR ortholog | 94.30% | 6685.0 |
| 11 | A2ARV4 | LDLR ortholog | 94.30% | 6693.0 |
| 12 | O75197 | LRP5 | 93.80% | 2529.0 |
| 13 | Q91VN0 | LDLR ortholog | 93.80% | 2528.0 |
| 14 | B5DFC9 | LDLR ortholog | 92.20% | 2506.0 |
| 15 | O88322 | LDLR ortholog | 92.20% | 2501.0 |
| 16 | P01131 | LDLR variant | 92.60% | 1135.0 |
| 17 | Q28832 | LDLR ortholog | 92.60% | 1135.0 |
| 18 | P35951 | LRP9 | 87.00% | 1073.0 |
| 19 | P35950 | LRP8 | 87.00% | 1077.0 |
| 20 | P98164 | LRP2 | 78.80% | 5365.0 |
AlphaFold structure: pLDDT score 75.81, 6651 residues, 29% high-confidence regions
Human LDLR is highly similar to other LDL receptor family members (VLDLR, LRP1–11) and shares close orthologs across mammals. Top interactors include cathepsins (endosomal/lysosomal), PCSK9 (regulator), and APOB (physiological ligand).
Transcription factor regulatory data
LDLR is not a transcription factor. LDLR (low-density lipoprotein receptor) is a cell surface receptor protein involved in cholesterol metabolism, not a transcriptional regulator.
Upstream regulators: TFs that regulate LDLR
Total upstream TF regulators: 36 (from CoLLECTRI database)
| TF | Regulation | Evidence | Confidence |
|---|---|---|---|
| SREBF1 | Activation | ExTRI, TRRUST, TFactS, NTNU Curated, DoRothEA_A | High |
| SP1 | Activation | TRRUST, TFactS, NTNU Curated, DoRothEA_A, ExTRI, HTRI | High |
| SREBF2 | Activation | Experimentally validated | High |
| EGR1 | Activation | Experimentally validated | High |
| CREB1 | Activation | NTNU Curated, ExTRI | High |
| ESR1 | Activation | ExTRI, GEREDB | High |
| CREBBP | Activation | Experimentally validated | High |
| KLF9 | Activation | Experimentally validated | High |
| CEBPG | Activation | Experimentally validated | High |
| HNF4A | Activation | Predicted | — |
| PPARA | Activation | Predicted | — |
| NFYA | Activation | Experimentally validated | Low |
| RXRA | Activation | Predicted | Low |
| ATF3 | Repression | DoRothEA_A, ExTRI, HTRI, TRRUST | High |
| PPARG | Repression | ExTRI, GEREDB, NTNU Curated | High |
| KLF13 | Repression | ExTRI, TRRUST, NTNU Curated | High |
| PPARGC1A | Repression | Experimentally validated | High |
| BMAL1 | Unknown | Experimentally validated | High |
| CEBPB | Unknown | Experimentally validated | High |
| SP3 | Unknown | Experimentally validated | High |
| HES1 | Unknown | Experimentally validated | High |
| HES6 | Unknown | Experimentally validated | High |
| IKZF1 | Unknown | Experimentally validated | High |
| YY1 | Unknown | Experimentally validated | High |
| ZBTB17 | Unknown | Experimentally validated | High |
| CEBPA | Unknown | Predicted | — |
| FOS | Unknown | Predicted | — |
| NR1H3 | Unknown | Predicted | — |
| THRB | Unknown | Predicted | — |
| CNBP | Unknown mechanism | Experimentally validated | High |
| HNRNPK | Unknown mechanism | Experimentally validated | High |
| TXK | Unknown mechanism | Experimentally validated | High |
| DNMT1 | Unknown mechanism | Predicted | Low |
| DGKQ | Unknown mechanism | Predicted | — |
| KLF4 | Unknown mechanism | Predicted | — |
Evidence types: ExTRI (experimental TF-target interactions), GEREDB (gene expression regulatory elements), NTNU Curated (manually curated), TRRUST (manually curated regulatory relationships), DoRothEA_A (predicted/ChIP-seq), TFactS (TF-gene associations), HTRI (human TF targets).
Based on my search of biobtree databases, here’s the pharmacology data for LDLR:
Drug & pharmacology data
LDLR as a drug target: YES — established target via PCSK9 inhibition
LDLR is targeted indirectly through PCSK9 inhibition. PCSK9 binds to LDLR and promotes its degradation; blocking this interaction with monoclonal antibodies or siRNA increases LDLR expression and LDL uptake.
Targeting molecules: ~17 ChEMBL entries + 445 PCSK9/LDLR interaction inhibitors
Approved drugs (Phase 4):
- EVOLOCUMAB (CHEMBL2364655) — Repatha — Antibody, anti-PCSK9, 113 clinical trials
- ALIROCUMAB (CHEMBL2109540) — Praluent — Antibody, anti-PCSK9, 84 clinical trials
Advanced candidates (Phase 3):
- INCLISIRAN (CHEMBL3990033) — Leqvio — Oligonucleotide (siRNA), anti-PCSK9, 43 clinical trials
- BOCOCIZUMAB (CHEMBL3137349) — Antibody, anti-PCSK9, 20 clinical trials
Additional direct LDLR targets: 17 preclinical/research molecules from ChEMBL (phase 0), mostly patent compounds with limited development.
Total molecules in ChEMBL: ~17 direct LDLR inhibitors; ~445 PCSK9/LDLR interaction disruptors
Clinical trials
Top approved/advanced interventions:
- Evolocumab: 113 trials (indications: hypercholesterolemia, familial FH, cardiovascular disease, myocardial infarction, stroke)
- Alirocumab: 84 trials (indications: hypercholesterolemia, FH, coronary artery disease, MI)
- Inclisiran: 43 trials (indications: hypercholesterolemia, cardiovascular disease, familial FH)
- Bococizumab: 20 trials (phase 3; similar indications)
Pharmacogenomics
- LDLR variants & drug response: 4,658 ClinVar disease-associated variants documented; variants cause familial hypercholesterolemia (FH), the primary indication for PCSK9 inhibitors
- Dosing guidelines: None specific to LDLR genotype; standard dosing for evolocumab (140 mg SC biweekly) and alirocumab (75 mg SC biweekly) applies across genotypes
- Known gene-drug interactions: Heterozygous LDLR mutations show reduced LDLR expression; PCSK9 inhibitors have greater LDL-lowering effect in patients with functional LDLR copies. Homozygous LDLR deficiency (no functional receptors) shows minimal response to PCSK9 inhibitors; requires alternative therapies (CETP inhibitors, lipoprotein apheresis)
Based on the biobtree expression data for LDLR, here’s the summary:
Expression profiles
Tissue Expression (Bgee)
LDLR shows ubiquitous expression across 281 of 295 conditions (94.9% present calls), with highest expression scores in endocrine and epithelial tissues.
| Rank | Tissue/Anatomical Region | Expression Score | Quality |
|---|---|---|---|
| 1 | Adrenal tissue | 99.53 | Gold |
| 2 | Lower lobe of lung | 97.66 | Gold |
| 3 | Right adrenal gland | 96.45 | Gold |
| 4 | Adrenal gland | 96.21 | Gold |
| 5 | Right adrenal gland cortex | 96.05 | Gold |
| 6 | Left adrenal gland | 95.85 | Gold |
| 7 | Endometrium epithelium | 95.75 | Gold |
| 8 | Olfactory segment of nasal mucosa | 95.66 | Gold |
| 9 | Adrenal cortex | 95.48 | Gold |
| 10 | Left adrenal gland cortex | 95.31 | Gold |
| 11 | Stromal cell of endometrium | 95.30 | Gold |
| 12 | Upper lobe of lung | 95.17 | Gold |
| 13 | Upper lobe of left lung | 95.09 | Gold |
| 14 | Lung | 94.52 | Gold |
| 15 | Mucosa of urinary bladder | 94.34 | Gold |
| 16 | Right lung | 93.94 | Gold |
| 17 | Esophagus mucosa | 93.66 | Gold |
| 18 | Lower esophagus mucosa | 93.61 | Gold |
| 19 | Islet of Langerhans | 93.28 | Gold |
| 20 | Left uterine tube | 93.21 | Gold |
| 21 | Pharyngeal mucosa | 92.79 | Gold |
| 22 | Mucosa of sigmoid colon | 92.79 | Gold |
| 23 | Ventricular zone | 92.77 | Gold |
| 24 | Cartilage tissue | 92.67 | Gold |
| 25 | Cervix epithelium | 92.43 | Gold |
| 26 | Liver | 92.39 | Gold |
| 27 | Decidua | 92.36 | Gold |
| 28 | Oral cavity | 92.09 | Gold |
| 29 | Gingival epithelium | 91.83 | Gold |
| 30 | Right ovary | 91.73 | Gold |
Tissue-specific patterns: Strong expression in steroid hormone-secreting tissues (adrenal gland > 95% of max), throughout respiratory epithelium (lung lobes ~94-97%), reproductive tissues (uterine tubes, endometrium ~93-95%), and gastrointestinal tract mucosae. Average expression score across all tissues: 81.62.
Single-Cell Expression Datasets
LDLR is present in major single-cell atlases:
| Dataset | Tissue/System | Cell Count | Cells with Expression |
|---|---|---|---|
| E-GEOD-130148 | Lung (Drop-seq) | 14,560 | Multiple cell types |
| E-MTAB-8060 | Human embryos (in vitro cultured) | 245,346 | Lineage-specific |
| E-MTAB-10596 | Dental follicle & organoids | 3,388 | Mesenchymal & epithelial |
| E-MTAB-3929 | Preimplantation embryos | 1,529 | Early developmental |
Cell-type enrichment: Expression appears highest in endothelial cells, hepatocytes, and macrophages (consistent with LDL uptake function), with broader expression in epithelial and mesenchymal populations across tissues.
Expression Summary
- Max score: 99.53 (adrenal tissue)
- Expression breadth: Ubiquitous (281/295 conditions)
- Data quality: 271/295 high-quality (gold standard) measurements
- Pattern: Liver and steroid hormone-secreting tissue enrichment; ubiquitous presence in epithelial and vascular tissues reflects role in systemic cholesterol homeostasis.
Disease associations
Mendelian / Monogenic Diseases
Familial Hypercholesterolemia Type 1 (Heterozygous)
- OMIM: 143890
- Mondo: MONDO:0007750
- Inheritance: Autosomal dominant
- Evidence: Definitive (Laboratory for Molecular Medicine); Strong (Genomics England PanelApp, Labcorp Genetics)
Homozygous Familial Hypercholesterolemia
- Orphanet: 391665
- Mondo: MONDO:0018328
- Inheritance: Autosomal recessive
- Evidence: Supportive (Orphanet)
Dysbetalipoproteinemia
- Orphanet: 412
- Mondo: MONDO:0018473 (hyperlipoproteinemia type 3)
- Inheritance: Not specified in available data
Smith-Lemli-Opitz Syndrome
- Orphanet: 818
- Mondo: MONDO:0010035
- Inheritance: Autosomal recessive (implied)
X-linked Intellectual Disability, Najm Type
- Orphanet: 163937
- Mondo: MONDO:0010417
- Inheritance: X-linked recessive
Additional Associated Mondo Terms
- MONDO:0005439 (Familial hypercholesterolemia - general)
- MONDO:0007751 (Hypercholesterolemia, autosomal dominant, type B)
- MONDO:0011374 (Hypercholesterolemia, familial, 4)
- MONDO:0021187 (Hyperlipidemia)
- MONDO:0008021 (Cowden syndrome 1)
Clinical Phenotypes (HPO Terms)
| Phenotype | HPO ID |
|---|---|
| Autosomal dominant inheritance | HP:0000006 |
| Autosomal recessive inheritance | HP:0000007 |
| Hypercholesterolemia | HP:0003124 |
| Increased LDL cholesterol concentration | HP:0003141 |
| Hyperlipidemia | HP:0003077 |
| Xanthomatosis | HP:0000991 |
| Tendon xanthomatosis | HP:0010874 |
| Xanthelasma | HP:0001114 |
| Corneal arcus | HP:0001084 |
| Myocardial infarction | HP:0001658 |
| Premature coronary artery atherosclerosis | HP:0005181 |
| Coronary artery atherosclerosis | HP:0001677 |
| Precocious atherosclerosis | HP:0004416 |
| Cerebral artery atherosclerosis | HP:0007201 |
| Coronary artery aneurysm | HP:0030882 |
| Angina pectoris | HP:0001681 |
| Sudden cardiac death | HP:0001645 |
| Supravalvular aortic stenosis | HP:0004381 |
| Abnormal left ventricular function | HP:0005162 |
| Heart murmur | HP:0030148 |
| Mitral regurgitation | HP:0001653 |
| Aortic atherosclerotic lesion | HP:0012397 |
| Calcification of the aorta | HP:0004963 |
| Premature arteriosclerosis | HP:0005177 |
| Peripheral arterial stenosis | HP:0004950 |
| Renal artery stenosis | HP:0001920 |
| Abnormal internal carotid artery morphology | HP:3000062 |
| Hypertension | HP:0000822 |
| Dyspnea | HP:0002094 |
| Optic neuropathy | HP:0001138 |
| Abnormal eye physiology | HP:0012373 |
GWAS Associations (Top 30 by Significance)
| Trait/Disease | Associated Variant | P-value | Study ID |
|---|---|---|---|
| LDL cholesterol | LDLR | 4.0e-262 | GCST002222_7 |
| Cholesterol, total | LDLR | 5.0e-202 | GCST002221_37 |
| Apolipoprotein B levels | LDLR | 2.0e-96 | GCST010243_149 |
| Low density lipoprotein cholesterol levels | LDLR/SMARCA4 | 1.0e-100 | GCST011347_11 |
| LDL cholesterol levels | LDLR | 4.0e-89 | GCST010245_144 |
| LDL cholesterol levels | SMARCA4 | 1.0e-96 | GCST008077_40 |
| LDL cholesterol | LDLR | 4.0e-117 | GCST000759_25 |
| Cholesterol, total | LDLR | 7.0e-97 | GCST000760_5 |
| Total cholesterol levels | LDLR/SMARCA4 | 3.0e-76 | GCST011346_13 |
| Medication use (HMG CoA reductase inhibitors) | LDLR | 8.0e-116 | GCST007931_11 |
| LDL cholesterol levels x long total sleep time interaction | LDLR/SMARCA4 | 7.0e-129 | GCST009366_51 |
| LDL cholesterol | SMARCA4 | 2.0e-51 | GCST000134_4 |
| Cholesterol, total | SPC24/LDLR | 8.0e-49 | GCST006034_28 |
| LDL cholesterol | LDLR | 2.0e-26 | GCST000287_2 |
| Cholesterol, total | LDLR | 9.0e-24 | GCST000285_5 |
| Coronary artery disease | LDLR/SMARCA4 | 9.0e-34 | GCST010866_161 |
| Coronary artery disease or large artery stroke | SMARCA4 | 2.0e-11 | GCST002290_4 |
| Lipoprotein-associated phospholipase A2 activity and mass | LDLR | 3.0e-11 | GCST001273_2 |
| Metabolite levels | LDLR | 4.0e-09 | GCST001639_5 |
| Myocardial infarction | LDLR/SMARCA4 | 6.0e-11 | GCST011364_28 |
| Abdominal aortic aneurysm | LDLR | 8.0e-14 | GCST003877_5 |
| Peripheral artery disease | LDLR/SMARCA4 | 1.0e-10 | GCST008474_20 |
| LDL cholesterol levels x short total sleep time interaction | LDLR | 1.0e-28 | GCST009365_54 |
| Lipoprotein (a) levels | LDLR/SMARCA4 | 3.0e-17 | GCST012232_33 |
| Serum metabolite levels (CMS) | LDLR | 1.0e-11 | GCST009240_323 |
| LDL cholesterol | LDLR | 7.0e-08 | GCST000975_11 |
| Carotid intima media thickness | LDLR | 1.0e-07 | GCST001231_11 |
| Disorders of lipid metabolism | LDLR/SMARCA4 | 3.0e-10 | GCST007480_1 |
| Coronary artery disease | LDLR | 5.0e-41 | GCST005194_123 |
| Aging traits (healthspan, parental lifespan or longevity) | LDLR | 4.0e-09 | GCST011100_22 |