Q5SW96 (ARH_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
Low density lipoprotein receptor adapter protein 1

Alternative name(s):
Autosomal recessive hypercholesterolemia protein

Gene names

Name:	LDLRAP1
Synonyms:	ARH

Organism

Homo sapiens (Human)

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Primates › Haplorrhini › Catarrhini › Hominidae › Homo

Protein attributes

Sequence length	308 AA.
Sequence status	Complete.
Protein existence	Evidence 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
Post-translational modification	Phosphorylated upon DNA damage, probably by ATM or ATR. Ref.10 Ref.11
Involvement in disease	Defects in LDLRAP1 are the cause of autosomal recessive hypercholesterolemia (ARH) [MIM:603813]. ARH is a disorder caused by defective internalization of LDL receptors (LDLR) in the liver. ARH has the clinical features of familial hypercholesterolemia (FH) [MIM:143890] homozygotes, including severely elevated plasma LDL cholesterol, tuberous and tendon xanthomata, and premature atherosclerosis. LDL receptor (LDLR) activity measured in skin fibroblasts is normal, as the LDL binding ability. Ref.1
Sequence similarities	Contains 1 PID domain.

Ontologies

Keywords
Biological process	Cholesterol metabolism Endocytosis Lipid metabolism Steroid metabolism
Cellular component	Cytoplasm
Coding sequence diversity	Polymorphism
Disease	Atherosclerosis Disease mutation Hyperlipidemia
PTM	Phosphoprotein
Technical term	3D-structure Complete proteome Reference proteome
Gene Ontology (GO)
Biological process	amyloid precursor protein metabolic process Inferred from mutant phenotype. Source: BHF-UCL cholesterol homeostasis Inferred from mutant phenotype. Source: BHF-UCL cholesterol metabolic process Non-traceable author statement Ref.7. Source: UniProtKB positive regulation of cholesterol metabolic process Inferred by curator. Source: BHF-UCL positive regulation of receptor-mediated endocytosis Inferred from mutant phenotype. Source: UniProtKB receptor internalization Inferred from mutant phenotype. Source: BHF-UCL receptor-mediated endocytosis of low-density lipoprotein particle involved in cholesterol transport Inferred from mutant phenotype Ref.2. Source: BHF-UCL regulation of establishment of protein localization in plasma membrane Inferred from mutant phenotype. Source: BHF-UCL regulation of protein binding Inferred from mutant phenotype. Source: UniProtKB
Cellular component	basal plasma membrane Inferred from direct assay Ref.7. Source: UniProtKB cytosol Inferred from direct assay Ref.7. Source: UniProtKB early endosome Inferred from direct assay. Source: UniProtKB internal side of plasma membrane Inferred from direct assay. Source: BHF-UCL neurofilament Inferred from sequence or structural similarity. Source: BHF-UCL recycling endosome Inferred from direct assay. Source: BHF-UCL
Molecular function	AP-2 adaptor complex binding Inferred from direct assay Ref.8. Source: BHF-UCL beta-amyloid binding Inferred from physical interaction. Source: BHF-UCL clathrin adaptor activity Inferred from direct assay Ref.8. Source: BHF-UCL low-density lipoprotein particle receptor binding Inferred from physical interaction Ref.6. 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 receptor signaling complex scaffold activity Inferred from mutant phenotype. Source: UniProtKB signaling adaptor activity Inferred from direct assay Ref.6. Source: BHF-UCL
Complete GO annotation...

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Chain

1 – 308

308

Low density lipoprotein receptor adapter protein 1

PRO_0000064675

Regions

Domain

42 – 196

155

PID

Region

249 – 276

28

AP-2 complex binding

Motif

212 – 216

5

Clathrin box

Motif

257 – 266

10

[DE]-X(1,2)-F-X-X-[FL]-X-X-X-R motif

Compositional bias

23 – 26

4

Poly-Gly

Amino acid modifications

Modified residue

14

1

Phosphoserine Ref.11

Modified residue

186

1

Phosphoserine Ref.10

Natural variations

Natural variant

202

1

S → H in ARH; Lebanon; requires 2 nucleotide substitutions. Ref.1

VAR_023320

Natural variant

202

1

S → P. Ref.1 Ref.2 Ref.3 Ref.5
Corresponds to variant rs6687605 [ dbSNP | Ensembl ].

VAR_028403

Experimental info

Mutagenesis

165

1

F → A: Abolishes LDLR cytoplasmic tail binding. Ref.6

Mutagenesis

165

1

F → V: Abolishes LDLR cytoplasmic tail binding. Ref.6

Mutagenesis

212 – 213

2

LL → AA: Abolishes clathrin binding.

Mutagenesis

214

1

D → A: Abolishes clathrin binding. Ref.6

Mutagenesis

216

1

E → A: Abolishes clathrin binding. Ref.6

Mutagenesis

256

1

D → R: Abolishes interaction with AP2B1. Ref.9

Mutagenesis

266

1

R → A: Abolishes AP-2 complex binding. Ref.6

Secondary structure

1

.

.

.

308

Helix Strand Turn

Details...

Helix

256 – 266

11

Sequences

	Sequence		Length	Mass (Da)
	Q5SW96 [UniParc]. Last modified October 17, 2006. Version 3. Checksum: DE83168CB328D2A7	FASTA	308	33,885
	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

References

	« Hide 'large scale' referencesShow '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: 11326085] [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: 12417523] [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: 17974005] [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. , 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: 16710414] [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: 15489334] [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: 12221107] [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: 12451172] [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: 15728179] [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: 16903783] [Abstract] Cited for: INTERACTION WITH AP2B1, MUTAGENESIS OF ASP-256.
[10]	"ATM and ATR substrate analysis reveals extensive protein networks responsive to DNA damage." Matsuoka S., Ballif B.A., Smogorzewska A., McDonald E.R. III, Hurov K.E., Luo J., Bakalarski C.E., Zhao Z., Solimini N., Lerenthal Y., Shiloh Y., Gygi S.P., Elledge S.J. Science 316:1160-1166(2007) [PubMed: 17525332] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-186, MASS SPECTROMETRY. Tissue: Embryonic kidney.
[11]	"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: 18669648] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-14, MASS SPECTROMETRY. Tissue: Cervix carcinoma.
[12]	"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: 21269460] [Abstract] Cited for: 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: 16516836] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (1.60 ANGSTROMS) OF 252-267 IN COMPLEX WITH AP2B1, DOMAIN.
+	Additional computationally mapped references.

Web resources

GeneReviews

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.

IPI

IPI00004758.

PIR

T17340.

RefSeq

NP_056442.2. NM_015627.2.

UniGene

Hs.590911.

3D structure databases

PDBe
RCSB PDB
PDBj

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
2G30	X-ray	1.60	P	252-267	[»]

ProteinModelPortal

Q5SW96.

SMR

Q5SW96. Positions 30-174.

ModBase

Search...

Protein-protein interaction databases

IntAct

Q5SW96. 1 interaction.

STRING

Q5SW96.

PTM databases

PhosphoSite

Q5SW96.

Polymorphism databases

DMDM

116241254.

Proteomic databases

PRIDE

Q5SW96.

Protocols and materials databases

StructuralBiologyKnowledgebase

Search...

Genome annotation databases

Ensembl

ENST00000374338; ENSP00000363458; ENSG00000157978.

GeneID

26119.

KEGG

hsa:26119.

UCSC

uc001bkl.2. human.

Organism-specific databases

CTD

26119.

GeneCards

GC01P025870.

H-InvDB

HIX0023695.

HGNC

HGNC:18640. LDLRAP1.

HPA

CAB003705.

MIM

603813. phenotype.
605747. gene.

neXtProt

NX_Q5SW96.

Orphanet

406. Familial hypercholesterolemia.

GenAtlas

Search...

Phylogenomic databases

eggNOG

prNOG09284.

HOGENOM

HBG444079.

HOVERGEN

HBG058060.

InParanoid

Q5SW96.

OMA

CTADKMH.

OrthoDB

EOG46Q6T7.

PhylomeDB

Q5SW96.

Gene expression databases

ArrayExpress

Q5SW96.

Bgee

Q5SW96.

CleanEx

HS_LDLRAP1.

Genevestigator

Q5SW96.

GermOnline

ENSG00000157978. Homo sapiens.

Family and domain databases

InterPro

IPR011993. PH_type.
IPR006020. PTyr_interaction_dom.
[Graphical view]

Gene3D

G3DSA:2.30.29.30. PH_type. 1 hit.

KO

K12474.

Pfam

PF00640. PID. 1 hit.
[Graphical view]

SMART

SM00462. PTB. 1 hit.
[Graphical view]

PROSITE

PS01179. PID. 1 hit.
[Graphical view]

ProtoNet

Search...

Other

NextBio

48126.

SOURCE

Search...

Entry information

Entry name

ARH_HUMAN

Accession

Primary (citable) accession number: Q5SW96
Secondary accession number(s): A2BHI5 , Q6TQS9, Q8N2Y0, Q9UFI9

Entry history

Integrated into UniProtKB/Swiss-Prot:	August 30, 2005
Last sequence update:	October 17, 2006
Last modified:	January 25, 2012
This is version 79 of the entry and version 3 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program

Disclaimer

Any 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.