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Protein

Low density lipoprotein receptor adapter protein 1

Gene

LDLRAP1

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: -Experimental evidence at protein leveli

Functioni

Adapter protein (clathrin-associated sorting protein (CLASP)) required for efficient endocytosis of the LDL receptor (LDLR) in polarized cells such as hepatocytes and lymphocytes, but not in non-polarized cells (fibroblasts). May be required for LDL binding and internalization but not for receptor clustering in coated pits. May facilitate the endocytocis of LDLR and LDLR-LDL complexes from coated pits by stabilizing the interaction between the receptor and the structural components of the pits. May also be involved in the internalization of other LDLR family members. Binds to phosphoinositides, which regulate clathrin bud assembly at the cell surface. Required for trafficking of LRP2 to the endocytic recycling compartment which is necessary for LRP2 proteolysis, releasing a tail fragment which translocates to the nucleus and mediates transcriptional repression (By similarity).By similarity1 Publication

GO - Molecular functioni

GO - Biological processi

Keywordsi

Biological processCholesterol metabolism, Endocytosis, Lipid metabolism, Steroid metabolism, Sterol metabolism

Enzyme and pathway databases

ReactomeiR-HSA-8856825 Cargo recognition for clathrin-mediated endocytosis
R-HSA-8856828 Clathrin-mediated endocytosis
R-HSA-8964026 Chylomicron clearance
R-HSA-8964038 LDL clearance

Protein family/group databases

MoonDBiQ5SW96 Curated

Names & Taxonomyi

Protein namesi
Recommended name:
Low density lipoprotein receptor adapter protein 1Curated
Alternative name(s):
Autosomal recessive hypercholesterolemia protein1 Publication
Gene namesi
Name:LDLRAP1Imported
Synonyms:ARH1 Publication
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
Proteomesi
  • UP000005640 Componenti: Chromosome 1

Organism-specific databases

EuPathDBiHostDB:ENSG00000157978.11
HGNCiHGNC:18640 LDLRAP1
MIMi605747 gene
neXtProtiNX_Q5SW96

Subcellular locationi

Extracellular region or secreted Cytosol Plasma membrane Cytoskeleton Lysosome Endosome Peroxisome ER Golgi apparatus Nucleus Mitochondrion Manual annotation Automatic computational assertionGraphics by Christian Stolte; Source: COMPARTMENTS

Keywords - Cellular componenti

Cytoplasm

Pathology & Biotechi

Involvement in diseasei

Hypercholesterolemia, autosomal recessive (ARH)1 Publication
The disease is caused by mutations affecting the gene represented in this entry.
Disease descriptionA familial condition characterized by elevated circulating cholesterol contained in either low-density lipoproteins alone or also in very-low-density lipoproteins.
See also OMIM:603813
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_023320202S → H in ARH; Lebanon; requires 2 nucleotide substitutions. 1 PublicationCorresponds to variant dbSNP:rs386629678EnsemblClinVar.1

Mutagenesis

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Mutagenesisi165F → A: Abolishes LDLR cytoplasmic tail binding. 1 Publication1
Mutagenesisi165F → V: Abolishes LDLR cytoplasmic tail binding. 1 Publication1
Mutagenesisi212 – 213LL → AA: Abolishes clathrin binding. 1 Publication2
Mutagenesisi214D → A: Abolishes clathrin binding. 1 Publication1
Mutagenesisi216E → A: Abolishes clathrin binding. 1 Publication1
Mutagenesisi256D → R: Abolishes interaction with AP2B1. 1 Publication1
Mutagenesisi266R → A: Abolishes AP-2 complex binding. 1 Publication1

Keywords - Diseasei

Atherosclerosis, Disease mutation, Hyperlipidemia

Organism-specific databases

DisGeNETi26119
MalaCardsiLDLRAP1
MIMi603813 phenotype
OpenTargetsiENSG00000157978
Orphaneti391665 Homozygous familial hypercholesterolemia
PharmGKBiPA128394641

Polymorphism and mutation databases

BioMutaiLDLRAP1
DMDMi116241254

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
ChainiPRO_00000646751 – 308Low density lipoprotein receptor adapter protein 1Add BLAST308

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Modified residuei1N-acetylmethionineCombined sources1
Modified residuei14PhosphoserineCombined sources1
Modified residuei186PhosphoserineCombined sources1
Modified residuei202PhosphoserineBy similarity1

Keywords - PTMi

Acetylation, Phosphoprotein

Proteomic databases

EPDiQ5SW96
MaxQBiQ5SW96
PaxDbiQ5SW96
PeptideAtlasiQ5SW96
PRIDEiQ5SW96
ProteomicsDBi63967

PTM databases

iPTMnetiQ5SW96
PhosphoSitePlusiQ5SW96

Expressioni

Tissue specificityi

Expressed at high levels in the kidney, liver, and placenta, with lower levels detectable in brain, heart, muscle, colon, spleen, intestine, lung, and leukocytes.

Gene expression databases

BgeeiENSG00000157978 Expressed in 218 organ(s), highest expression level in right hemisphere of cerebellum
CleanExiHS_LDLRAP1
GenevisibleiQ5SW96 HS

Organism-specific databases

HPAiCAB003705
HPA050358

Interactioni

Subunit structurei

Interacts (via PID domain) with LDLR (via NPXY motif) (PubMed:12221107). Binds to soluble clathrin trimers (PubMed:12221107). Interacts with AP2B1; the interaction mediates the association with the AP-2 complex (PubMed:12221107). Interacts with VLDLR (By similarity). Interacts with LRP2 (By similarity).By similarity1 Publication

Binary interactionsi

GO - Molecular functioni

Protein-protein interaction databases

BioGridi117561, 13 interactors
ELMiQ5SW96
IntActiQ5SW96, 18 interactors
MINTiQ5SW96
STRINGi9606.ENSP00000363458

Structurei

Secondary structure

1308
Legend: HelixTurnBeta strandPDB Structure known for this area
Show more details

3D structure databases

ProteinModelPortaliQ5SW96
SMRiQ5SW96
ModBaseiSearch...
MobiDBiSearch...

Miscellaneous databases

EvolutionaryTraceiQ5SW96

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Domaini42 – 196PIDPROSITE-ProRule annotationAdd BLAST155

Region

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Regioni249 – 276AP-2 complex binding1 PublicationAdd BLAST28

Motif

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Motifi212 – 216Clathrin box1 Publication5
Motifi257 – 266[DE]-X(1,2)-F-X-X-[FL]-X-X-X-R motif1 Publication10

Compositional bias

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Compositional biasi23 – 26Poly-Gly4

Domaini

The [DE]-X(1,2)-F-X-X-[FL]-X-X-X-R motif mediates interaction the AP-2 complex subunit AP2B1.1 Publication
The PID domain mediates interaction with the NPXY internalization motif of LDLR.By similarity

Phylogenomic databases

eggNOGiKOG3536 Eukaryota
ENOG410ZHJT LUCA
GeneTreeiENSGT00530000062937
HOGENOMiHOG000030906
HOVERGENiHBG058060
InParanoidiQ5SW96
KOiK12474
OMAiFEFWQVS
OrthoDBiEOG091G0TOH
PhylomeDBiQ5SW96
TreeFamiTF314159

Family and domain databases

Gene3Di2.30.29.30, 1 hit
InterProiView protein in InterPro
IPR011993 PH-like_dom_sf
IPR006020 PTB/PI_dom
PfamiView protein in Pfam
PF00640 PID, 1 hit
SMARTiView protein in SMART
SM00462 PTB, 1 hit
PROSITEiView protein in PROSITE
PS01179 PID, 1 hit

Sequencei

Sequence statusi: Complete.

Q5SW96-1 [UniParc]FASTAAdd to basket
« Hide
        10         20         30         40         50
MDALKSAGRA LIRSPSLAKQ SWGGGGRHRK LPENWTDTRE TLLEGMLFSL
60 70 80 90 100
KYLGMTLVEQ PKGEELSAAA IKRIVATAKA SGKKLQKVTL KVSPRGIILT
110 120 130 140 150
DNLTNQLIEN VSIYRISYCT ADKMHDKVFA YIAQSQHNQS LECHAFLCTK
160 170 180 190 200
RKMAQAVTLT VAQAFKVAFE FWQVSKEEKE KRDKASQEGG DVLGARQDCT
210 220 230 240 250
PSLKSLVATG NLLDLEETAK APLSTVSANT TNMDEVPRPQ ALSGSSVVWE
260 270 280 290 300
LDDGLDEAFS RLAQSRTNPQ VLDTGLTAQD MHYAQCLSPV DWDKPDSSGT

EQDDLFSF
Length:308
Mass (Da):33,885
Last modified:October 17, 2006 - v3
Checksum:iDE83168CB328D2A7
GO

Natural variant

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_07692556T → M Probable disease-associated mutation found in patients with hypercholesterolemia. 1 PublicationCorresponds to variant dbSNP:rs752849346Ensembl.1
Natural variantiVAR_023320202S → H in ARH; Lebanon; requires 2 nucleotide substitutions. 1 PublicationCorresponds to variant dbSNP:rs386629678EnsemblClinVar.1
Natural variantiVAR_028403202S → P5 PublicationsCorresponds to variant dbSNP:rs6687605EnsemblClinVar.1

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AY389348 Genomic DNA Translation: AAQ90407.1
AL117654 mRNA Translation: CAB56030.2
AL606491 Genomic DNA No translation available.
BX572623 Genomic DNA No translation available.
BC029770 mRNA Translation: AAH29770.2
CCDSiCCDS30639.1
PIRiT17340
RefSeqiNP_056442.2, NM_015627.2
UniGeneiHs.590911

Genome annotation databases

EnsembliENST00000374338; ENSP00000363458; ENSG00000157978
GeneIDi26119
KEGGihsa:26119
UCSCiuc001bkl.5 human

Keywords - Coding sequence diversityi

Polymorphism

Similar proteinsi

Entry informationi

Entry nameiARH_HUMAN
AccessioniPrimary (citable) accession number: Q5SW96
Secondary accession number(s): A2BHI5
, Q6TQS9, Q8N2Y0, Q9UFI9
Entry historyiIntegrated into UniProtKB/Swiss-Prot: August 30, 2005
Last sequence update: October 17, 2006
Last modified: September 12, 2018
This is version 141 of the entry and version 3 of the sequence. See complete history.
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program
DisclaimerAny medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.

Miscellaneousi

Keywords - Technical termi

3D-structure, Complete proteome, Reference proteome
UniProt is an ELIXIR core data resource
Main funding by: National Institutes of Health

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