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Q5SW96

- ARH_HUMAN

UniProt

Q5SW96 - ARH_HUMAN

Protein

Low density lipoprotein receptor adapter protein 1

Gene

LDLRAP1

Organism
Homo sapiens (Human)
Status
Reviewed - Annotation score: 5 out of 5- Experimental evidence at protein leveli
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    • History
      Entry version 104 (01 Oct 2014)
      Sequence version 3 (17 Oct 2006)
      Previous versions | rss
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    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

    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

    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.1 Publication
    Note: The disease is caused by mutations affecting the gene represented in this entry.
    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.By similarity

    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.
    ModBaseiSearch...
    MobiDBiSearch...

    Miscellaneous databases

    EvolutionaryTraceiQ5SW96.

    Family & Domainsi

    Domains and Repeats

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Domaini42 – 196155PIDPROSITE-ProRule annotationAdd
    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.PROSITE-ProRule annotation

    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

    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: October 1, 2014
    This is version 104 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