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Q5SW96 (ARH_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Last modified July 9, 2014. Version 103. Feed History...

Clusters with 100%, 90%, 50% identity | Documents (6) | Third-party data text xml rdf/xml gff fasta
to top of pageNames·Attributes·General annotation·Ontologies·Interactions·Sequence annotation·Sequences·References·Cross-refs·Entry info·DocumentsCustomize order

Names and origin

Protein namesRecommended name:
Low density lipoprotein receptor adapter protein 1
Alternative name(s):
Autosomal recessive hypercholesterolemia protein
Gene names
Name:LDLRAP1
Synonyms:ARH
OrganismHomo sapiens (Human) [Reference proteome]
Taxonomic identifier9606 [NCBI]
Taxonomic lineageEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo

Protein attributes

Sequence length308 AA.
Sequence statusComplete.
Protein existenceEvidence at protein level

General annotation (Comments)

Function

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. Ref.8

Subunit structure

Interacts with LDLR. Binds to soluble clathrin trimers. Interacts with AP2B1; the interaction mediates the association with the AP-2 complex. Interacts with VLDLR By similarity. Ref.6 Ref.7 Ref.8 Ref.9

Subcellular location

Cytoplasm Ref.7.

Tissue specificity

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

Domain

The [DE]-X(1,2)-F-X-X-[FL]-X-X-X-R motif mediates interaction the AP-2 complex subunit AP2B1. Ref.13

Involvement in disease

Hypercholesterolemia, autosomal recessive (ARH) [MIM:603813]: A familial condition characterized by elevated circulating cholesterol contained in either low-density lipoproteins alone or also in very-low-density lipoproteins.
Note: The disease is caused by mutations affecting the gene represented in this entry. Ref.1

Sequence similarities

Contains 1 PID domain.

Ontologies

Keywords
   Biological processCholesterol metabolism
Endocytosis
Lipid metabolism
Steroid metabolism
Sterol metabolism
   Cellular componentCytoplasm
   Coding sequence diversityPolymorphism
   DiseaseAtherosclerosis
Disease mutation
Hyperlipidemia
   PTMAcetylation
Phosphoprotein
   Technical term3D-structure
Complete proteome
Reference proteome
Gene Ontology (GO)
   Biological_processamyloid precursor protein metabolic process

Inferred from mutant phenotype PubMed 12805363. Source: BHF-UCL

cholesterol homeostasis

Inferred from mutant phenotype PubMed 15166224. Source: BHF-UCL

cholesterol metabolic process

Non-traceable author statement Ref.7. Source: UniProtKB

positive regulation of cholesterol metabolic process

Inferred by curator PubMed 15166224. Source: BHF-UCL

positive regulation of receptor-mediated endocytosis

Inferred from mutant phenotype PubMed 15166224. Source: UniProtKB

positive regulation of signal transduction

Inferred from direct assay Ref.6. Source: GOC

receptor internalization

Inferred from mutant phenotype PubMed 15166224. Source: BHF-UCL

receptor-mediated endocytosis

Inferred from direct assay PubMed 14528014. Source: BHF-UCL

receptor-mediated endocytosis of low-density lipoprotein particle involved in cholesterol transport

Inferred from mutant phenotype Ref.2PubMed 12464675PubMed 15166224. Source: BHF-UCL

regulation of establishment of protein localization to plasma membrane

Inferred from mutant phenotype PubMed 12805363. Source: BHF-UCL

regulation of protein binding

Inferred from mutant phenotype PubMed 15166224. Source: UniProtKB

transport

Non-traceable author statement Ref.7. Source: UniProtKB

   Cellular_componentaxon

Inferred from sequence or structural similarity. Source: BHF-UCL

basal plasma membrane

Inferred from direct assay Ref.7. Source: UniProtKB

cytoplasmic side of plasma membrane

Inferred from direct assay PubMed 14528014. Source: BHF-UCL

cytosol

Inferred from direct assay Ref.7. Source: UniProtKB

early endosome

Inferred from direct assay PubMed 14528014. Source: UniProtKB

neurofilament

Inferred from sequence or structural similarity PubMed 17727637. Source: BHF-UCL

recycling endosome

Inferred from direct assay PubMed 14528014. Source: BHF-UCL

   Molecular_functionAP-2 adaptor complex binding

Inferred from direct assay Ref.8. Source: BHF-UCL

beta-amyloid binding

Inferred from physical interaction PubMed 12805363. Source: BHF-UCL

clathrin adaptor activity

Inferred from direct assay Ref.8. Source: BHF-UCL

clathrin binding

Inferred from direct assay Ref.7. Source: UniProtKB

low-density lipoprotein particle receptor binding

Inferred from physical interaction Ref.6PubMed 14528014. Source: BHF-UCL

phosphatidylinositol-4,5-bisphosphate binding

Inferred from direct assay Ref.7. Source: BHF-UCL

phosphotyrosine binding

Inferred from direct assay Ref.7. Source: UniProtKB

protein binding

Inferred from physical interaction Ref.6PubMed 16189514. Source: IntAct

receptor signaling complex scaffold activity

Inferred from mutant phenotype PubMed 15166224. Source: UniProtKB

signaling adaptor activity

Inferred from direct assay Ref.6. Source: BHF-UCL

Complete GO annotation...

Binary interactions

With

Entry

#Exp.

IntAct

Notes

AP2B1P630103EBI-747813,EBI-432924

Sequence annotation (Features)

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Chain1 – 308308Low density lipoprotein receptor adapter protein 1
PRO_0000064675

Regions

Domain42 – 196155PID
Region249 – 27628AP-2 complex binding
Motif212 – 2165Clathrin box
Motif257 – 26610[DE]-X(1,2)-F-X-X-[FL]-X-X-X-R motif
Compositional bias23 – 264Poly-Gly

Amino acid modifications

Modified residue11N-acetylmethionine Ref.12
Modified residue141Phosphoserine Ref.10

Natural variations

Natural variant2021S → H in ARH; Lebanon; requires 2 nucleotide substitutions. Ref.1
VAR_023320
Natural variant2021S → P. Ref.1 Ref.2 Ref.3 Ref.5
Corresponds to variant rs6687605 [ dbSNP | Ensembl ].
VAR_028403

Experimental info

Mutagenesis1651F → A: Abolishes LDLR cytoplasmic tail binding. Ref.6
Mutagenesis1651F → V: Abolishes LDLR cytoplasmic tail binding. Ref.6
Mutagenesis212 – 2132LL → AA: Abolishes clathrin binding.
Mutagenesis2141D → A: Abolishes clathrin binding. Ref.6
Mutagenesis2161E → A: Abolishes clathrin binding. Ref.6
Mutagenesis2561D → R: Abolishes interaction with AP2B1. Ref.9
Mutagenesis2661R → A: Abolishes AP-2 complex binding. Ref.6

Secondary structure

... 308
Helix Strand Turn

Details...

Sequences

Sequence LengthMass (Da)Tools
Q5SW96 [UniParc].

Last modified October 17, 2006. Version 3.
Checksum: DE83168CB328D2A7

FASTA30833,885
        10         20         30         40         50         60 
MDALKSAGRA LIRSPSLAKQ SWGGGGRHRK LPENWTDTRE TLLEGMLFSL KYLGMTLVEQ 

        70         80         90        100        110        120 
PKGEELSAAA IKRIVATAKA SGKKLQKVTL KVSPRGIILT DNLTNQLIEN VSIYRISYCT 

       130        140        150        160        170        180 
ADKMHDKVFA YIAQSQHNQS LECHAFLCTK RKMAQAVTLT VAQAFKVAFE FWQVSKEEKE 

       190        200        210        220        230        240 
KRDKASQEGG DVLGARQDCT PSLKSLVATG NLLDLEETAK APLSTVSANT TNMDEVPRPQ 

       250        260        270        280        290        300 
ALSGSSVVWE LDDGLDEAFS RLAQSRTNPQ VLDTGLTAQD MHYAQCLSPV DWDKPDSSGT 


EQDDLFSF 

« Hide

References

« Hide 'large scale' references
[1]"Autosomal recessive hypercholesterolemia caused by mutations in a putative LDL receptor adaptor protein."
Garcia C.K., Wilund K.R., Arca M., Zuliani G., Fellin R., Maioli M., Calandra S., Bertolini S., Cossu F., Grishin N., Barnes R., Cohen J.C., Hobbs H.H.
Science 292:1394-1398(2001) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA], VARIANT PRO-202, VARIANT ARH HIS-202.
[2]"Molecular mechanisms of autosomal recessive hypercholesterolemia."
Wilund K.R., Yi M., Campagna F., Arca M., Zuliani G., Fellin R., Ho Y.K., Garcia J.V., Hobbs H.H., Cohen J.C.
Hum. Mol. Genet. 11:3019-3030(2002) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA], VARIANT PRO-202.
[3]"The full-ORF clone resource of the German cDNA consortium."
Bechtel S., Rosenfelder H., Duda A., Schmidt C.P., Ernst U., Wellenreuther R., Mehrle A., Schuster C., Bahr A., Bloecker H., Heubner D., Hoerlein A., Michel G., Wedler H., Koehrer K., Ottenwaelder B., Poustka A., Wiemann S., Schupp I.
BMC Genomics 8:399-399(2007) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA], VARIANT PRO-202.
Tissue: Uterus.
[4]"The DNA sequence and biological annotation of human chromosome 1."
Gregory S.G., Barlow K.F., McLay K.E., Kaul R., Swarbreck D., Dunham A., Scott C.E., Howe K.L., Woodfine K., Spencer C.C.A., Jones M.C., Gillson C., Searle S., Zhou Y., Kokocinski F., McDonald L., Evans R., Phillips K. expand/collapse author list , Atkinson A., Cooper R., Jones C., Hall R.E., Andrews T.D., Lloyd C., Ainscough R., Almeida J.P., Ambrose K.D., Anderson F., Andrew R.W., Ashwell R.I.S., Aubin K., Babbage A.K., Bagguley C.L., Bailey J., Beasley H., Bethel G., Bird C.P., Bray-Allen S., Brown J.Y., Brown A.J., Buckley D., Burton J., Bye J., Carder C., Chapman J.C., Clark S.Y., Clarke G., Clee C., Cobley V., Collier R.E., Corby N., Coville G.J., Davies J., Deadman R., Dunn M., Earthrowl M., Ellington A.G., Errington H., Frankish A., Frankland J., French L., Garner P., Garnett J., Gay L., Ghori M.R.J., Gibson R., Gilby L.M., Gillett W., Glithero R.J., Grafham D.V., Griffiths C., Griffiths-Jones S., Grocock R., Hammond S., Harrison E.S.I., Hart E., Haugen E., Heath P.D., Holmes S., Holt K., Howden P.J., Hunt A.R., Hunt S.E., Hunter G., Isherwood J., James R., Johnson C., Johnson D., Joy A., Kay M., Kershaw J.K., Kibukawa M., Kimberley A.M., King A., Knights A.J., Lad H., Laird G., Lawlor S., Leongamornlert D.A., Lloyd D.M., Loveland J., Lovell J., Lush M.J., Lyne R., Martin S., Mashreghi-Mohammadi M., Matthews L., Matthews N.S.W., McLaren S., Milne S., Mistry S., Moore M.J.F., Nickerson T., O'Dell C.N., Oliver K., Palmeiri A., Palmer S.A., Parker A., Patel D., Pearce A.V., Peck A.I., Pelan S., Phelps K., Phillimore B.J., Plumb R., Rajan J., Raymond C., Rouse G., Saenphimmachak C., Sehra H.K., Sheridan E., Shownkeen R., Sims S., Skuce C.D., Smith M., Steward C., Subramanian S., Sycamore N., Tracey A., Tromans A., Van Helmond Z., Wall M., Wallis J.M., White S., Whitehead S.L., Wilkinson J.E., Willey D.L., Williams H., Wilming L., Wray P.W., Wu Z., Coulson A., Vaudin M., Sulston J.E., Durbin R.M., Hubbard T., Wooster R., Dunham I., Carter N.P., McVean G., Ross M.T., Harrow J., Olson M.V., Beck S., Rogers J., Bentley D.R.
Nature 441:315-321(2006) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[5]"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)."
The MGC Project Team
Genome Res. 14:2121-2127(2004) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA], VARIANT PRO-202.
Tissue: Brain.
[6]"ARH is a modular adaptor protein that interacts with the LDL receptor, clathrin, and AP-2."
He G., Gupta S., Yi M., Michaely P., Hobbs H.H., Cohen J.C.
J. Biol. Chem. 277:44044-44049(2002) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH LDLR; CLATHRIN AND AP-2 COMPLEX, MUTAGENESIS OF PHE-165; 212-LEU-LEU-213; ASP-214; GLU-216 AND ARG-266.
[7]"The autosomal recessive hypercholesterolemia (ARH) protein interfaces directly with the clathrin-coat machinery."
Mishra S.K., Watkins S.C., Traub L.M.
Proc. Natl. Acad. Sci. U.S.A. 99:16099-16104(2002) [PubMed] [Europe PMC] [Abstract]
Cited for: CHARACTERIZATION, INTERACTION WITH CLATHRIN AND AP-2 COMPLEX, SUBCELLULAR LOCATION.
[8]"Functional dissection of an AP-2 beta2 appendage-binding sequence within the autosomal recessive hypercholesterolemia protein."
Mishra S.K., Keyel P.A., Edeling M.A., Dupin A.L., Owen D.J., Traub L.M.
J. Biol. Chem. 280:19270-19280(2005) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION, INTERACTION WITH AP2B1.
[9]"Role of the AP2 beta-appendage hub in recruiting partners for clathrin-coated vesicle assembly."
Schmid E.M., Ford M.G.J., Burtey A., Praefcke G.J.K., Peak-Chew S.-Y., Mills I.G., Benmerah A., McMahon H.T.
PLoS Biol. 4:E262-E262(2006) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH AP2B1, MUTAGENESIS OF ASP-256.
[10]"A quantitative atlas of mitotic phosphorylation."
Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E., Elledge S.J., Gygi S.P.
Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008) [PubMed] [Europe PMC] [Abstract]
Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-14, IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
Tissue: Cervix carcinoma.
[11]"Initial characterization of the human central proteome."
Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J.
BMC Syst. Biol. 5:17-17(2011) [PubMed] [Europe PMC] [Abstract]
Cited for: IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
[12]"N-terminal acetylome analyses and functional insights of the N-terminal acetyltransferase NatB."
Van Damme P., Lasa M., Polevoda B., Gazquez C., Elosegui-Artola A., Kim D.S., De Juan-Pardo E., Demeyer K., Hole K., Larrea E., Timmerman E., Prieto J., Arnesen T., Sherman F., Gevaert K., Aldabe R.
Proc. Natl. Acad. Sci. U.S.A. 109:12449-12454(2012) [PubMed] [Europe PMC] [Abstract]
Cited for: ACETYLATION [LARGE SCALE ANALYSIS] AT MET-1, IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
[13]"Molecular switches involving the AP-2 beta2 appendage regulate endocytic cargo selection and clathrin coat assembly."
Edeling M.A., Mishra S.K., Keyel P.A., Steinhauser A.L., Collins B.M., Roth R., Heuser J.E., Owen D.J., Traub L.M.
Dev. Cell 10:329-342(2006) [PubMed] [Europe PMC] [Abstract]
Cited for: X-RAY CRYSTALLOGRAPHY (1.60 ANGSTROMS) OF 252-267 IN COMPLEX WITH AP2B1, DOMAIN.
+Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ
AY389348 Genomic DNA. Translation: AAQ90407.1.
AL117654 mRNA. Translation: CAB56030.2.
AL606491, BX572623 Genomic DNA. Translation: CAI16483.1.
BX572623, AL606491 Genomic DNA. Translation: CAM12863.1.
BC029770 mRNA. Translation: AAH29770.2.
CCDSCCDS30639.1.
PIRT17340.
RefSeqNP_056442.2. NM_015627.2.
UniGeneHs.590911.

3D structure databases

PDBe
RCSB-PDB
PDBj
EntryMethodResolution (Å)ChainPositionsPDBsum
2G30X-ray1.60P252-267[»]
ProteinModelPortalQ5SW96.
SMRQ5SW96. Positions 43-175.
ModBaseSearch...
MobiDBSearch...

Protein-protein interaction databases

BioGrid117561. 6 interactions.
IntActQ5SW96. 5 interactions.
STRING9606.ENSP00000363458.

PTM databases

PhosphoSiteQ5SW96.

Polymorphism databases

DMDM116241254.

Proteomic databases

MaxQBQ5SW96.
PaxDbQ5SW96.
PRIDEQ5SW96.

Protocols and materials databases

DNASU26119.
StructuralBiologyKnowledgebaseSearch...

Genome annotation databases

EnsemblENST00000374338; ENSP00000363458; ENSG00000157978.
GeneID26119.
KEGGhsa:26119.
UCSCuc001bkl.4. human.

Organism-specific databases

CTD26119.
GeneCardsGC01P025870.
H-InvDBHIX0023695.
HGNCHGNC:18640. LDLRAP1.
HPACAB003705.
MIM603813. phenotype.
605747. gene.
neXtProtNX_Q5SW96.
Orphanet391665. Homozygous familial hypercholesterolemia.
PharmGKBPA128394641.
GenAtlasSearch...

Phylogenomic databases

eggNOGNOG305324.
HOGENOMHOG000030906.
HOVERGENHBG058060.
InParanoidQ5SW96.
KOK12474.
OMAWELDDGL.
OrthoDBEOG7RZ5QP.
PhylomeDBQ5SW96.
TreeFamTF314159.

Gene expression databases

BgeeQ5SW96.
CleanExHS_LDLRAP1.
GenevestigatorQ5SW96.

Family and domain databases

Gene3D2.30.29.30. 1 hit.
InterProIPR011993. PH_like_dom.
IPR006020. PTB/PI_dom.
[Graphical view]
PfamPF00640. PID. 1 hit.
[Graphical view]
SMARTSM00462. PTB. 1 hit.
[Graphical view]
PROSITEPS01179. PID. 1 hit.
[Graphical view]
ProtoNetSearch...

Other

EvolutionaryTraceQ5SW96.
GeneWikiLow_density_lipoprotein_receptor_adapter_protein_1.
GenomeRNAi26119.
NextBio48126.
PROQ5SW96.
SOURCESearch...

Entry information

Entry nameARH_HUMAN
AccessionPrimary (citable) accession number: Q5SW96
Secondary accession number(s): A2BHI5 expand/collapse secondary AC list , Q6TQS9, Q8N2Y0, Q9UFI9
Entry history
Integrated into UniProtKB/Swiss-Prot: August 30, 2005
Last sequence update: October 17, 2006
Last modified: July 9, 2014
This is version 103 of the entry and version 3 of the sequence. [Complete history]
Entry statusReviewed (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.

Relevant documents

SIMILARITY comments

Index of protein domains and families

PDB cross-references

Index of Protein Data Bank (PDB) cross-references

MIM cross-references

Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot

Human polymorphisms and disease mutations

Index of human polymorphisms and disease mutations

Human entries with polymorphisms or disease mutations

List of human entries with polymorphisms or disease mutations

Human chromosome 1

Human chromosome 1: entries, gene names and cross-references to MIM