LRP2 LDL receptor related protein 2 [Homo sapiens (human)] - Gene

Summary

Official Symbol: LRP2provided by HGNC
Official Full Name: LDL receptor related protein 2provided by HGNC
Primary source: HGNC:HGNC:6694
See related: Ensembl:ENSG00000081479 MIM:600073; AllianceGenome:HGNC:6694
Gene type: protein coding
RefSeq status: REVIEWED
Organism: Homo sapiens
Lineage: Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo
Also known as: DBS; GP330; LRP-2
Summary: The protein encoded by this gene, low density lipoprotein-related protein 2 (LRP2) or megalin, is a multi-ligand endocytic receptor that is expressed in many different tissues but primarily in absorptive epithilial tissues such as the kidney. This glycoprotein has a large amino-terminal extracellular domain, a single transmembrane domain, and a short carboxy-terminal cytoplasmic tail. The extracellular ligand-binding-domains bind diverse macromolecules including albumin, apolipoproteins B and E, and lipoprotein lipase. The LRP2 protein is critical for the reuptake of numerous ligands, including lipoproteins, sterols, vitamin-binding proteins, and hormones. This protein also has a role in cell-signaling; extracellular ligands include parathyroid horomones and the morphogen sonic hedgehog while cytosolic ligands include MAP kinase scaffold proteins and JNK interacting proteins. Recycling of this membrane receptor is regulated by phosphorylation of its cytoplasmic domain. Mutations in this gene cause Donnai-Barrow syndrome (DBS) and facio-oculoacoustico-renal syndrome (FOAR).[provided by RefSeq, Aug 2009]
Expression: Biased expression in kidney (RPKM 33.6), thyroid (RPKM 14.6) and 1 other tissue See more
Orthologs: mouse all
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Genomic context

Location:: 2q31.1

Exon count:: 81

Annotation release	Status	Assembly	Chr	Location
RS_2023_10	current	GRCh38.p14 (GCF_000001405.40)	2	NC_000002.12 (169127109..169362534, complement)
RS_2023_10	current	T2T-CHM13v2.0 (GCF_009914755.1)	2	NC_060926.1 (169602803..169838534, complement)
105.20220307	previous assembly	GRCh37.p13 (GCF_000001405.25)	2	NC_000002.11 (169983619..170219044, complement)

Chromosome 2 - NC_000002.12 Genomic Context describing neighboring genes

Genomic regions, transcripts, and products

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Go to reference sequence details

Genomic Sequence:

Go to nucleotide: Graphics FASTA GenBank

Expression

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See details

Project title: HPA RNA-seq normal tissues
Description: RNA-seq was performed of tissue samples from 95 human individuals representing 27 different tissues in order to determine tissue-specificity of all protein-coding genes
BioProject: PRJEB4337
Publication: PMID 24309898
Analysis date: Wed Apr 4 07:08:55 2018

Bibliography

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GeneRIFs: Gene References Into Functions

What's a GeneRIF?

Human parietal epithelial cells (PECs) and proteinuria in lupus nephritis: a role for ClC-5, megalin, and cubilin?
Title: Human parietal epithelial cells (PECs) and proteinuria in lupus nephritis: a role for ClC-5, megalin, and cubilin?
Proprotein convertase subtilisin/kexin type 9 targets megalin in the kidney proximal tubule and aggravates proteinuria in nephrotic syndrome.
Title: Proprotein convertase subtilisin/kexin type 9 targets megalin in the kidney proximal tubule and aggravates proteinuria in nephrotic syndrome.
Variants of LRP2, encoding a multifunctional cell-surface endocytic receptor, associated with hearing loss and retinal dystrophy.
Title: Variants of LRP2, encoding a multifunctional cell-surface endocytic receptor, associated with hearing loss and retinal dystrophy.
Regulation of Prostate Androgens by Megalin and 25-hydroxyvitamin D Status: Mechanism for High Prostate Androgens in African American Men.
Title: Regulation of Prostate Androgens by Megalin and 25-hydroxyvitamin D Status: Mechanism for High Prostate Androgens in African American Men.
The endocytosis receptor megalin: From bench to bedside.
Title: The endocytosis receptor megalin: From bench to bedside.
Structures of LRP2 reveal a molecular machine for endocytosis.
Title: Structures of LRP2 reveal a molecular machine for endocytosis.
Urinary A- and C-megalin predict progression of diabetic kidney disease: an exploratory retrospective cohort study.
Title: Urinary A- and C-megalin predict progression of diabetic kidney disease: an exploratory retrospective cohort study.
Renal Megalin mRNA Downregulation Is Associated with CKD Progression in IgA Nephropathy.
Title: Renal Megalin mRNA Downregulation Is Associated with CKD Progression in IgA Nephropathy.
Disturbed expression of vitamin D and retinoic acid-related orphan receptors alpha and gamma and of megalin in inflammatory skin diseases.
Title: Disturbed expression of vitamin D and retinoic acid-related orphan receptors α and γ and of megalin in inflammatory skin diseases.
Expanding the phenotypic spectrum of mutations in LRP2: a novel candidate gene of non-syndromic familial comitant strabismus.
Title: Expanding the phenotypic spectrum of mutations in LRP2: a novel candidate gene of non-syndromic familial comitant strabismus.

Submit: New GeneRIF Correction See all GeneRIFs (90)

Phenotypes

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Find tests for this gene in the NIH Genetic Testing Registry (GTR)

Review eQTL and phenotype association data in this region using PheGenI

Associated conditions

Description	Tests
Donnai-Barrow syndrome MedGen: C1857277 OMIM: 222448 GeneReviews: Donnai-Barrow Syndrome	Compare labs

EBI GWAS Catalog

Description
A genome-wide association study on common SNPs and rare CNVs in anorexia nervosa. EBI GWAS Catalog EBI GWAS CatalogPubMed
Gene-Smoking Interactions Identify Several Novel Blood Pressure Loci in the Framingham Heart Study. EBI GWAS Catalog EBI GWAS CatalogPubMed
Genome-wide association study of hematological and biochemical traits in a Japanese population. EBI GWAS Catalog EBI GWAS CatalogPubMed

Variation

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See variants in ClinVar

See studies and variants in dbVar

See Variation Viewer (GRCh37.p13)

See Variation Viewer (GRCh38)

Interactions

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Products	Interactant	Other Gene	Complex	Source	Pubs	Description

General gene information

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Markers

WI-17537 (e-PCR)
- UniSTS:26882

SHGC-80045 (e-PCR)
- UniSTS:101654

LRP2_7816 (e-PCR)
- UniSTS:467751

G32722 (e-PCR)
- UniSTS:117304

D2S2879 (e-PCR)
- UniSTS:1344

A009P03 (e-PCR)
- UniSTS:2385

D2S1416 (e-PCR)
- UniSTS:75117

RH124065 (e-PCR)
- UniSTS:138872

RH45139 (e-PCR)
- UniSTS:26027

RH123671 (e-PCR)
- UniSTS:138681

RH120397 (e-PCR)
- UniSTS:132540

Gene Ontology Provided by GOA

Function	Evidence Code	Pubs
enables SH3 domain binding	IEA Inferred from Electronic Annotation more info
enables calcium ion binding	IDA Inferred from Direct Assay more info	PubMed
enables cargo receptor activity	EXP Inferred from Experiment more info	PubMed
enables cargo receptor activity	TAS Traceable Author Statement more info
enables hormone binding	IBA Inferred from Biological aspect of Ancestor more info
enables insulin-like growth factor I binding	ISS Inferred from Sequence or Structural Similarity more info
enables low-density lipoprotein particle receptor activity	TAS Traceable Author Statement more info
enables protein binding	IPI Inferred from Physical Interaction more info	PubMed
enables protein transporter activity	ISS Inferred from Sequence or Structural Similarity more info
enables protein-folding chaperone binding	IPI Inferred from Physical Interaction more info	PubMed
enables protein-folding chaperone binding	ISS Inferred from Sequence or Structural Similarity more info	PubMed

Process	Evidence Code	Pubs
involved_in amyloid-beta clearance	ISS Inferred from Sequence or Structural Similarity more info
involved_in aorta development	IEA Inferred from Electronic Annotation more info
involved_in cell population proliferation	IEA Inferred from Electronic Annotation more info
involved_in cellular response to growth factor stimulus	ISS Inferred from Sequence or Structural Similarity more info
involved_in cobalamin transport	TAS Traceable Author Statement more info
involved_in coronary artery morphogenesis	ISS Inferred from Sequence or Structural Similarity more info
involved_in diol metabolic process	IEA Inferred from Electronic Annotation more info
involved_in endocytosis	TAS Traceable Author Statement more info	PubMed
involved_in folate import across plasma membrane	ISS Inferred from Sequence or Structural Similarity more info
involved_in forebrain development	IEA Inferred from Electronic Annotation more info
involved_in kidney development	IEA Inferred from Electronic Annotation more info
involved_in lipid metabolic process	TAS Traceable Author Statement more info	PubMed
involved_in male gonad development	ISS Inferred from Sequence or Structural Similarity more info
involved_in metal ion transport	IDA Inferred from Direct Assay more info	PubMed
involved_in negative regulation of BMP signaling pathway	ISS Inferred from Sequence or Structural Similarity more info
acts_upstream_of negative regulation of apoptotic process	IGI Inferred from Genetic Interaction more info	PubMed
involved_in neural tube closure	ISS Inferred from Sequence or Structural Similarity more info
involved_in neuron projection arborization	ISS Inferred from Sequence or Structural Similarity more info
involved_in outflow tract septum morphogenesis	ISS Inferred from Sequence or Structural Similarity more info
involved_in phosphatidylinositol 3-kinase/protein kinase B signal transduction	IGI Inferred from Genetic Interaction more info	PubMed
involved_in positive regulation of lysosomal protein catabolic process	ISS Inferred from Sequence or Structural Similarity more info	PubMed
involved_in positive regulation of neurogenesis	ISS Inferred from Sequence or Structural Similarity more info
involved_in positive regulation of oligodendrocyte progenitor proliferation	ISS Inferred from Sequence or Structural Similarity more info
involved_in protein transport	IDA Inferred from Direct Assay more info	PubMed
involved_in pulmonary artery morphogenesis	ISS Inferred from Sequence or Structural Similarity more info
involved_in receptor-mediated endocytosis	IBA Inferred from Biological aspect of Ancestor more info
involved_in receptor-mediated endocytosis	IDA Inferred from Direct Assay more info	PubMed
involved_in receptor-mediated endocytosis	ISS Inferred from Sequence or Structural Similarity more info	PubMed
involved_in response to leptin	IDA Inferred from Direct Assay more info	PubMed
involved_in retinoid metabolic process	TAS Traceable Author Statement more info
involved_in secondary heart field specification	ISS Inferred from Sequence or Structural Similarity more info
involved_in sensory perception of sound	ISS Inferred from Sequence or Structural Similarity more info
involved_in transcytosis	ISS Inferred from Sequence or Structural Similarity more info
involved_in transport across blood-brain barrier	NAS Non-traceable Author Statement more info	PubMed
involved_in vagina development	ISS Inferred from Sequence or Structural Similarity more info
involved_in ventricular compact myocardium morphogenesis	ISS Inferred from Sequence or Structural Similarity more info
involved_in ventricular septum development	IEA Inferred from Electronic Annotation more info
involved_in vitamin D metabolic process	TAS Traceable Author Statement more info

Component	Evidence Code	Pubs
located_in Golgi apparatus	IEA Inferred from Electronic Annotation more info
is_active_in apical plasma membrane	IBA Inferred from Biological aspect of Ancestor more info
located_in apical plasma membrane	IDA Inferred from Direct Assay more info	PubMed
located_in apical plasma membrane	ISS Inferred from Sequence or Structural Similarity more info
located_in axon	ISS Inferred from Sequence or Structural Similarity more info
located_in brush border membrane	ISS Inferred from Sequence or Structural Similarity more info
located_in clathrin-coated endocytic vesicle membrane	TAS Traceable Author Statement more info
located_in clathrin-coated pit	IEA Inferred from Electronic Annotation more info
located_in dendrite	ISS Inferred from Sequence or Structural Similarity more info
located_in endoplasmic reticulum	IEA Inferred from Electronic Annotation more info
located_in endosome lumen	IEA Inferred from Electronic Annotation more info
located_in external side of plasma membrane	ISS Inferred from Sequence or Structural Similarity more info
located_in extracellular exosome	HDA more info	PubMed
located_in lysosomal membrane	HDA more info	PubMed
located_in lysosome	TAS Traceable Author Statement more info	PubMed
is_active_in plasma membrane	IBA Inferred from Biological aspect of Ancestor more info
located_in plasma membrane	TAS Traceable Author Statement more info
part_of receptor complex	IBA Inferred from Biological aspect of Ancestor more info
part_of receptor complex	IDA Inferred from Direct Assay more info	PubMed
part_of receptor complex	ISS Inferred from Sequence or Structural Similarity more info

General protein information

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Preferred Names: low-density lipoprotein receptor-related protein 2

Names: Heymann nephritis antigen homolog; calcium sensor protein; glycoprotein 330; megalin

NCBI Reference Sequences (RefSeq)

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RefSeqs maintained independently of Annotated Genomes

These reference sequences exist independently of genome builds. Explain

These reference sequences are curated independently of the genome annotation cycle, so their versions may not match the RefSeq versions in the current genome build. Identify version mismatches by comparing the version of the RefSeq in this section to the one reported in Genomic regions, transcripts, and products above.

Genomic

NG_012634.1 RefSeqGene

Range

5079..240504

Download

GenBank, FASTA, Sequence Viewer (Graphics), LRG_1300

mRNA and Protein(s)

NM_004525.3 → NP_004516.2 low-density lipoprotein receptor-related protein 2 precursor

See identical proteins and their annotated locations for NP_004516.2

Status: REVIEWED

Source sequence(s)

AC007556, AY265357, AY265358, CD673312, DA200673, DA339827, DA401915, U33837

Consensus CDS

CCDS2232.1

UniProtKB/Swiss-Prot

O00711, P98164, Q16215

UniProtKB/TrEMBL

Q7Z5C0

Related

ENSP00000496870.1, ENST00000649046.1

Conserved Domains (12) summary

smart00192
Location:2905 → 2937

LDLa; Low-density lipoprotein receptor domain class A

smart00135
Location:1501 → 1543

LY; Low-density lipoprotein-receptor YWTD domain

smart00179
Location:4007 → 4047

EGF_CA; Calcium-binding EGF-like domain

COG3391
Location:2092 → 2285

YncE; DNA-binding beta-propeller fold protein YncE [General function prediction only]

cd00112
Location:3759 → 3793

LDLa; Low Density Lipoprotein Receptor Class A domain, a cysteine-rich repeat that plays a central role in mammalian cholesterol metabolism; the receptor protein binds LDL and transports it into cells by endocytosis; 7 successive cysteine-rich repeats of about ...

cd05819
Location:2097 → 2142

NHL; NHL repeat [structural motif]

pfam00057
Location:2863 → 2895

Ldl_recept_a; Low-density lipoprotein receptor domain class A

pfam00058
Location:4197 → 4237

Ldl_recept_b; Low-density lipoprotein receptor repeat class B

pfam12662
Location:3132 → 3155

cEGF; Complement Clr-like EGF-like

pfam14670
Location:2346 → 2382

FXa_inhibition; Coagulation Factor Xa inhibitory site

cl00057
Location:3147 → 3190

vWFA; Von Willebrand factor type A (vWA) domain was originally found in the blood coagulation protein von Willebrand factor (vWF). Typically, the vWA domain is made up of approximately 200 amino acid residues folded into a classic a/b para-rossmann type of ...

cl18310
Location:2091 → 2300

NHL; NHL repeat unit of beta-propeller proteins

RefSeqs of Annotated Genomes: GCF_000001405.40-RS_2023_10

The following sections contain reference sequences that belong to a specific genome build. Explain

Reference GRCh38.p14 Primary Assembly

Genomic

NC_000002.12 Reference GRCh38.p14 Primary Assembly

Range

169127109..169362534 complement

Download

GenBank, FASTA, Sequence Viewer (Graphics)

mRNA and Protein(s)

XM_011511183.4 → XP_011509485.1 low-density lipoprotein receptor-related protein 2 isoform X1

UniProtKB/TrEMBL

Q7Z5C0

Conserved Domains (12) summary

smart00192
Location:2905 → 2937

LDLa; Low-density lipoprotein receptor domain class A

smart00135
Location:1501 → 1543

LY; Low-density lipoprotein-receptor YWTD domain

smart00179
Location:3964 → 4004

EGF_CA; Calcium-binding EGF-like domain

COG3391
Location:2092 → 2285

YncE; DNA-binding beta-propeller fold protein YncE [General function prediction only]

cd00112
Location:3716 → 3750

LDLa; Low Density Lipoprotein Receptor Class A domain, a cysteine-rich repeat that plays a central role in mammalian cholesterol metabolism; the receptor protein binds LDL and transports it into cells by endocytosis; 7 successive cysteine-rich repeats of about ...

cd05819
Location:2097 → 2142

NHL; NHL repeat [structural motif]

pfam00057
Location:2863 → 2895

Ldl_recept_a; Low-density lipoprotein receptor domain class A

pfam00058
Location:4154 → 4194

Ldl_recept_b; Low-density lipoprotein receptor repeat class B

pfam12662
Location:3132 → 3155

cEGF; Complement Clr-like EGF-like

pfam14670
Location:2346 → 2382

FXa_inhibition; Coagulation Factor Xa inhibitory site

cl00057
Location:3147 → 3190

vWFA; Von Willebrand factor type A (vWA) domain was originally found in the blood coagulation protein von Willebrand factor (vWF). Typically, the vWA domain is made up of approximately 200 amino acid residues folded into a classic a/b para-rossmann type of ...

cl18310
Location:2091 → 2300

NHL; NHL repeat unit of beta-propeller proteins
XM_047444340.1 → XP_047300296.1 low-density lipoprotein receptor-related protein 2 isoform X2
XM_011511184.3 → XP_011509486.1 low-density lipoprotein receptor-related protein 2 isoform X3

UniProtKB/TrEMBL

Q4ZG84

Conserved Domains (12) summary

smart00192
Location:2142 → 2174

LDLa; Low-density lipoprotein receptor domain class A

smart00135
Location:738 → 780

LY; Low-density lipoprotein-receptor YWTD domain

smart00179
Location:3244 → 3284

EGF_CA; Calcium-binding EGF-like domain

COG3391
Location:1329 → 1522

YncE; DNA-binding beta-propeller fold protein YncE [General function prediction only]

cd00112
Location:2996 → 3030

LDLa; Low Density Lipoprotein Receptor Class A domain, a cysteine-rich repeat that plays a central role in mammalian cholesterol metabolism; the receptor protein binds LDL and transports it into cells by endocytosis; 7 successive cysteine-rich repeats of about ...

cd05819
Location:1334 → 1379

NHL; NHL repeat [structural motif]

pfam00057
Location:2100 → 2132

Ldl_recept_a; Low-density lipoprotein receptor domain class A

pfam00058
Location:3434 → 3474

Ldl_recept_b; Low-density lipoprotein receptor repeat class B

pfam12662
Location:2369 → 2392

cEGF; Complement Clr-like EGF-like

pfam14670
Location:1583 → 1619

FXa_inhibition; Coagulation Factor Xa inhibitory site

cl00057
Location:2384 → 2427

vWFA; Von Willebrand factor type A (vWA) domain was originally found in the blood coagulation protein von Willebrand factor (vWF). Typically, the vWA domain is made up of approximately 200 amino acid residues folded into a classic a/b para-rossmann type of ...

cl18310
Location:1328 → 1537

NHL; NHL repeat unit of beta-propeller proteins

Alternate T2T-CHM13v2.0

Genomic

NC_060926.1 Alternate T2T-CHM13v2.0

Range

169602803..169838534 complement

Download

GenBank, FASTA, Sequence Viewer (Graphics)

mRNA and Protein(s)

XM_054342042.1 → XP_054198017.1 low-density lipoprotein receptor-related protein 2 isoform X1
XM_054342043.1 → XP_054198018.1 low-density lipoprotein receptor-related protein 2 isoform X2
XM_054342044.1 → XP_054198019.1 low-density lipoprotein receptor-related protein 2 isoform X3