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Q5SW96

- ARH_HUMAN

UniProt

Q5SW96 - ARH_HUMAN

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Protein

Low density lipoprotein receptor adapter protein 1

Gene
LDLRAP1, ARH
Organism
Homo sapiens (Human)
Status
Reviewed - Annotation score: 5 out of 5 - 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.1 Publication

GO - Molecular functioni

  1. AP-2 adaptor complex binding Source: BHF-UCL
  2. beta-amyloid binding Source: BHF-UCL
  3. clathrin adaptor activity Source: BHF-UCL
  4. clathrin binding Source: UniProtKB
  5. low-density lipoprotein particle receptor binding Source: BHF-UCL
  6. phosphatidylinositol-4,5-bisphosphate binding Source: BHF-UCL
  7. phosphotyrosine binding Source: UniProtKB
  8. protein binding Source: IntAct
  9. receptor signaling complex scaffold activity Source: UniProtKB
  10. signaling adaptor activity Source: BHF-UCL

GO - Biological processi

  1. amyloid precursor protein metabolic process Source: BHF-UCL
  2. cholesterol homeostasis Source: BHF-UCL
  3. cholesterol metabolic process Source: UniProtKB
  4. positive regulation of cholesterol metabolic process Source: BHF-UCL
  5. positive regulation of receptor-mediated endocytosis Source: UniProtKB
  6. positive regulation of signal transduction Source: GOC
  7. receptor internalization Source: BHF-UCL
  8. receptor-mediated endocytosis Source: BHF-UCL
  9. receptor-mediated endocytosis of low-density lipoprotein particle involved in cholesterol transport Source: BHF-UCL
  10. regulation of establishment of protein localization to plasma membrane Source: BHF-UCL
  11. regulation of protein binding Source: UniProtKB
  12. transport Source: UniProtKB
Complete GO annotation...

Keywords - Biological processi

Cholesterol metabolism, Endocytosis, Lipid metabolism, Steroid metabolism, Sterol metabolism

Names & Taxonomyi

Protein namesi
Recommended name:
Low density lipoprotein receptor adapter protein 1
Alternative name(s):
Autosomal recessive hypercholesterolemia protein
Gene namesi
Name:LDLRAP1
Synonyms:ARH
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
ProteomesiUP000005640: Chromosome 1

Organism-specific databases

HGNCiHGNC:18640. LDLRAP1.

Subcellular locationi

Cytoplasm 1 Publication

GO - Cellular componenti

  1. axon Source: BHF-UCL
  2. basal plasma membrane Source: UniProtKB
  3. cytoplasmic side of plasma membrane Source: BHF-UCL
  4. cytosol Source: UniProtKB
  5. early endosome Source: UniProtKB
  6. neurofilament Source: BHF-UCL
  7. recycling endosome Source: BHF-UCL
Complete GO annotation...

Keywords - Cellular componenti

Cytoplasm

Pathology & Biotechi

Involvement in diseasei

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.1 Publication
Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Natural varianti202 – 2021S → H in ARH; Lebanon; requires 2 nucleotide substitutions. 1 Publication
VAR_023320

Mutagenesis

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Mutagenesisi165 – 1651F → A: Abolishes LDLR cytoplasmic tail binding. 1 Publication
Mutagenesisi165 – 1651F → V: Abolishes LDLR cytoplasmic tail binding. 1 Publication
Mutagenesisi212 – 2132LL → AA: Abolishes clathrin binding.
Mutagenesisi214 – 2141D → A: Abolishes clathrin binding. 1 Publication
Mutagenesisi216 – 2161E → A: Abolishes clathrin binding. 1 Publication
Mutagenesisi256 – 2561D → R: Abolishes interaction with AP2B1. 1 Publication
Mutagenesisi266 – 2661R → A: Abolishes AP-2 complex binding. 1 Publication

Keywords - Diseasei

Atherosclerosis, Disease mutation, Hyperlipidemia

Organism-specific databases

MIMi603813. phenotype.
Orphaneti391665. Homozygous familial hypercholesterolemia.
PharmGKBiPA128394641.

PTM / Processingi

Molecule processing

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Chaini1 – 308308Low density lipoprotein receptor adapter protein 1PRO_0000064675Add
BLAST

Amino acid modifications

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Modified residuei1 – 11N-acetylmethionine1 Publication
Modified residuei14 – 141Phosphoserine1 Publication

Keywords - PTMi

Acetylation, Phosphoprotein

Proteomic databases

MaxQBiQ5SW96.
PaxDbiQ5SW96.
PRIDEiQ5SW96.

PTM databases

PhosphoSiteiQ5SW96.

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

BgeeiQ5SW96.
CleanExiHS_LDLRAP1.
GenevestigatoriQ5SW96.

Organism-specific databases

HPAiCAB003705.

Interactioni

Subunit structurei

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.4 Publications

Binary interactionsi

WithEntry#Exp.IntActNotes
AP2B1P630103EBI-747813,EBI-432924

Protein-protein interaction databases

BioGridi117561. 6 interactions.
IntActiQ5SW96. 5 interactions.
STRINGi9606.ENSP00000363458.

Structurei

Secondary structure

1
308
Legend: HelixTurnBeta strand
Show more details
Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Helixi256 – 26611

3D structure databases

Select the link destinations:
PDBe
RCSB PDB
PDBj
Links Updated
EntryMethodResolution (Å)ChainPositionsPDBsum
2G30X-ray1.60P252-267[»]
ProteinModelPortaliQ5SW96.
SMRiQ5SW96. Positions 43-175.

Miscellaneous databases

EvolutionaryTraceiQ5SW96.

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Domaini42 – 196155PIDAdd
BLAST

Region

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Regioni249 – 27628AP-2 complex bindingAdd
BLAST

Motif

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Motifi212 – 2165Clathrin box
Motifi257 – 26610[DE]-X(1,2)-F-X-X-[FL]-X-X-X-R motif

Compositional bias

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Compositional biasi23 – 264Poly-Gly

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

Sequence similaritiesi

Contains 1 PID domain.

Phylogenomic databases

eggNOGiNOG305324.
HOGENOMiHOG000030906.
HOVERGENiHBG058060.
InParanoidiQ5SW96.
KOiK12474.
OMAiWELDDGL.
OrthoDBiEOG7RZ5QP.
PhylomeDBiQ5SW96.
TreeFamiTF314159.

Family and domain databases

Gene3Di2.30.29.30. 1 hit.
InterProiIPR011993. PH_like_dom.
IPR006020. PTB/PI_dom.
[Graphical view]
PfamiPF00640. PID. 1 hit.
[Graphical view]
SMARTiSM00462. PTB. 1 hit.
[Graphical view]
PROSITEiPS01179. PID. 1 hit.
[Graphical view]

Sequencei

Sequence statusi: Complete.

Q5SW96-1 [UniParc]FASTAAdd to Basket

« Hide

MDALKSAGRA LIRSPSLAKQ SWGGGGRHRK LPENWTDTRE TLLEGMLFSL    50
KYLGMTLVEQ PKGEELSAAA IKRIVATAKA SGKKLQKVTL KVSPRGIILT 100
DNLTNQLIEN VSIYRISYCT ADKMHDKVFA YIAQSQHNQS LECHAFLCTK 150
RKMAQAVTLT VAQAFKVAFE FWQVSKEEKE KRDKASQEGG DVLGARQDCT 200
PSLKSLVATG NLLDLEETAK APLSTVSANT TNMDEVPRPQ ALSGSSVVWE 250
LDDGLDEAFS RLAQSRTNPQ VLDTGLTAQD MHYAQCLSPV DWDKPDSSGT 300
EQDDLFSF 308
Length:308
Mass (Da):33,885
Last modified:October 17, 2006 - v3
Checksum:iDE83168CB328D2A7
GO

Natural variant

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Natural varianti202 – 2021S → H in ARH; Lebanon; requires 2 nucleotide substitutions. 1 Publication
VAR_023320
Natural varianti202 – 2021S → P.4 Publications
Corresponds to variant rs6687605 [ dbSNP | Ensembl ].
VAR_028403

Sequence databases

Select the link destinations:
EMBL
GenBank
DDBJ
Links Updated
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.
CCDSiCCDS30639.1.
PIRiT17340.
RefSeqiNP_056442.2. NM_015627.2.
UniGeneiHs.590911.

Genome annotation databases

EnsembliENST00000374338; ENSP00000363458; ENSG00000157978.
GeneIDi26119.
KEGGihsa:26119.
UCSCiuc001bkl.4. human.

Polymorphism databases

DMDMi116241254.

Keywords - Coding sequence diversityi

Polymorphism

Cross-referencesi

Sequence databases

Select the link destinations:
EMBL
GenBank
DDBJ
Links Updated
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 .
CCDSi CCDS30639.1.
PIRi T17340.
RefSeqi NP_056442.2. NM_015627.2.
UniGenei Hs.590911.

3D structure databases

Select the link destinations:
PDBe
RCSB PDB
PDBj
Links Updated
Entry Method Resolution (Å) Chain Positions PDBsum
2G30 X-ray 1.60 P 252-267 [» ]
ProteinModelPortali Q5SW96.
SMRi Q5SW96. Positions 43-175.
ModBasei Search...
MobiDBi Search...

Protein-protein interaction databases

BioGridi 117561. 6 interactions.
IntActi Q5SW96. 5 interactions.
STRINGi 9606.ENSP00000363458.

PTM databases

PhosphoSitei Q5SW96.

Polymorphism databases

DMDMi 116241254.

Proteomic databases

MaxQBi Q5SW96.
PaxDbi Q5SW96.
PRIDEi Q5SW96.

Protocols and materials databases

DNASUi 26119.
Structural Biology Knowledgebase Search...

Genome annotation databases

Ensembli ENST00000374338 ; ENSP00000363458 ; ENSG00000157978 .
GeneIDi 26119.
KEGGi hsa:26119.
UCSCi uc001bkl.4. human.

Organism-specific databases

CTDi 26119.
GeneCardsi GC01P025870.
H-InvDB HIX0023695.
HGNCi HGNC:18640. LDLRAP1.
HPAi CAB003705.
MIMi 603813. phenotype.
605747. gene.
neXtProti NX_Q5SW96.
Orphaneti 391665. Homozygous familial hypercholesterolemia.
PharmGKBi PA128394641.
GenAtlasi Search...

Phylogenomic databases

eggNOGi NOG305324.
HOGENOMi HOG000030906.
HOVERGENi HBG058060.
InParanoidi Q5SW96.
KOi K12474.
OMAi WELDDGL.
OrthoDBi EOG7RZ5QP.
PhylomeDBi Q5SW96.
TreeFami TF314159.

Miscellaneous databases

EvolutionaryTracei Q5SW96.
GeneWikii Low_density_lipoprotein_receptor_adapter_protein_1.
GenomeRNAii 26119.
NextBioi 48126.
PROi Q5SW96.
SOURCEi Search...

Gene expression databases

Bgeei Q5SW96.
CleanExi HS_LDLRAP1.
Genevestigatori Q5SW96.

Family and domain databases

Gene3Di 2.30.29.30. 1 hit.
InterProi IPR011993. PH_like_dom.
IPR006020. PTB/PI_dom.
[Graphical view ]
Pfami PF00640. PID. 1 hit.
[Graphical view ]
SMARTi SM00462. PTB. 1 hit.
[Graphical view ]
PROSITEi PS01179. PID. 1 hit.
[Graphical view ]
ProtoNeti Search...

Publicationsi

« Hide 'large scale' publications
  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. Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA], VARIANT PRO-202.
  3. 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.
    , 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. Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-14, IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
    Tissue: Cervix carcinoma.
  11. Cited for: IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
  12. 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.

Entry informationi

Entry nameiARH_HUMAN
AccessioniPrimary (citable) accession number: Q5SW96
Secondary accession number(s): A2BHI5
, Q6TQS9, Q8N2Y0, Q9UFI9
Entry historyi
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 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

Documents

  1. Human chromosome 1
    Human chromosome 1: entries, gene names and cross-references to MIM
  2. Human entries with polymorphisms or disease mutations
    List of human entries with polymorphisms or disease mutations
  3. Human polymorphisms and disease mutations
    Index of human polymorphisms and disease mutations
  4. MIM cross-references
    Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot
  5. PDB cross-references
    Index of Protein Data Bank (PDB) cross-references
  6. SIMILARITY comments
    Index of protein domains and families

External Data

Dasty 3

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