Reviewed, UniProtKB/Swiss-Prot O43520 (AT8B1_HUMAN)

Names and origin

Protein names

Recommended name:
    Probable phospholipid-transporting ATPase IC
    EC=3.6.3.1
Alternative name(s):
    Familial intrahepatic cholestasis type 1
    ATPase class I type 8B member 1

Gene names

Name:	ATP8B1
Synonyms:	ATPIC, FIC1, PFIC

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	1251 AA.
Sequence status	Complete.
Sequence processing	The displayed sequence is not processed.
Protein existence	Evidence at protein level.

General annotation (Comments)

Function	May play a role in the transport of aminophospholipids from the outer to the inner leaflet of various membranes and the maintenance of asymmetric distribution of phospholipids in the canicular membrane. May have a role in transport of bile acids into the canaliculus, uptake of bile acids from intestinal contents into intestinal mucosa or both.
Catalytic activity	ATP + H2O + phospholipid(In) = ADP + phosphate + phospholipid(Out).
Subcellular location	Membrane; Multi-pass membrane protein.
Tissue specificity	Found in most tissues except brain and skeletal muscle. Most abundant in pancreas and small intestine.
Involvement in disease	Defects in ATP8B1 are the cause of progressive familial intrahepatic cholestasis type 1 (PFIC1) [MIM:211600]; also known as Byler disease. PFIC1 is an autosomal recessive disorder, characterized by early infancy cholestasis, that may be initially episodic but progresses to malnutrition, growth retardation and end-stage liver disease before adulthood. Ref.1 Ref.6 Ref.7 Defects in ATP8B1 are the cause of benign recurrent intrahepatic cholestasis type 1 (BRIC1) [MIM:243300]; also known as Summerskill syndrome. BRIC is characterized by intermittent episodes of cholestasis without progression to liver failure. There is initial elevation of serum bile acids, followed by cholestatic jaundice which generally spontaneously resolves after periods of weeks to months. The cholestatic attacks vary in severity and duration. Patients are asymptomatic between episodes, both clinically and biochemically. Ref.1 Ref.7 Ref.5 Defects in ATP8B1 can be associated with intrahepatic cholestasis of pregnancy (ICP) [MIM:147480]; also known as pregnancy-related cholestasis. ICP is a multifactorial liver disorder of pregnancy. It presents during the second or, more commonly, the third trimestre of pregnancy with intense pruritus which becomes more severe with advancing gestation and cholestasis. Cholestasis results from abnormal biliary transport from the liver into the small intestine. ICP causes fetal distress, spontaneous premature delivery and intrauterine death. ICP patients have spontaneous and progressive disappearance of cholestasis after delivery. Ref.8 Ref.9
Sequence similarities	Belongs to the cation transport ATPase (P-type) family. Type IV subfamily.

Ontologies

Keywords
Cellular component	Membrane
Coding sequence diversity	Polymorphism
Disease	Disease mutation Intrahepatic cholestasis
Domain	Transmembrane
Ligand	ATP-binding Magnesium Metal-binding Nucleotide-binding
Molecular function	Hydrolase
PTM	Phosphoprotein
Gene Ontology (GO)
Biological process	ATP biosynthetic process Inferred from electronic annotation. Source: InterPro bile acid and bile salt transport Non-traceable author statement. Source: UniProtKB negative regulation of transcription Inferred from mutant phenotype. Source: UniProtKB phospholipid transport Inferred from electronic annotation. Source: InterPro
Cellular component	apical plasma membrane Inferred from direct assay. Source: UniProtKB integral to plasma membrane Non-traceable author statement. Source: UniProtKB membrane fraction Inferred from direct assay. Source: UniProtKB
Molecular function	ATP binding Inferred from electronic annotation. Source: UniProtKB-KW ATPase activity, coupled to transmembrane movement of ions, phosphorylative mechanism Inferred from electronic annotation. Source: InterPro magnesium ion binding Inferred from electronic annotation. Source: UniProtKB-KW phospholipid-translocating ATPase activity Traceable author statement. Source: UniProtKB
Complete GO annotation...

Sequence annotation (Features)

	Feature key	Position(s)	Length	Description	Graphical view	Feature identifier
Molecule processing
	Chain	1 – 1251	1251	Probable phospholipid-transporting ATPase IC		PRO_0000046364
Regions
	Topological domain	1 – 108	108	Cytoplasmic Potential
	Transmembrane	109 – 130	22	Potential
	Topological domain	131 – 136	6	Extracellular Potential
	Transmembrane	137 – 156	20	Potential
	Topological domain	157 – 340	184	Cytoplasmic Potential
	Transmembrane	341 – 362	22	Potential
	Topological domain	363 – 389	27	Extracellular Potential
	Transmembrane	390 – 411	22	Potential
	Topological domain	412 – 949	538	Cytoplasmic Potential
	Transmembrane	950 – 970	21	Potential
	Topological domain	971 – 982	12	Extracellular Potential
	Transmembrane	983 – 1002	20	Potential
	Topological domain	1003 – 1032	30	Cytoplasmic Potential
	Transmembrane	1033 – 1054	22	Potential
	Topological domain	1055 – 1068	14	Extracellular Potential
	Transmembrane	1069 – 1091	23	Potential
	Topological domain	1092 – 1097	6	Cytoplasmic Potential
	Transmembrane	1098 – 1118	21	Potential
	Topological domain	1119 – 1138	20	Extracellular Potential
	Transmembrane	1139 – 1163	25	Potential
	Topological domain	1164 – 1251	88	Cytoplasmic Potential
Sites
	Active site	454	1	4-aspartylphosphate intermediate By similarity
	Metal binding	893	1	Magnesium By similarity
	Metal binding	897	1	Magnesium By similarity
Natural variations
	Natural variant	45	1	N → T in ICP. Ref.8		VAR_043044
	Natural variant	70	1	D → N in BRIC1; compound heterozygote with Q-600; uncertain pathological significance; may be associated with ICP. dbSNP rs34719006. Ref.7		VAR_043045
	Natural variant	78	1	H → Q: dbSNP rs3745079.		VAR_029271
	Natural variant	127	1	L → P in PFIC1. Ref.7		VAR_043046
	Natural variant	203	1	K → E in ICP. Ref.8		VAR_043047
	Natural variant	288	1	L → S in PFIC1. Ref.1		VAR_008809
	Natural variant	305	1	F → I Ref.9		VAR_043048
	Natural variant	308	1	G → D in BRIC1. dbSNP rs28939685. Ref.7		VAR_043049
	Natural variant	308	1	G → V in PFIC1. Ref.1		VAR_008810
	Natural variant	344	1	I → F in BRIC1. Ref.7		VAR_043050
	Natural variant	384	1	R → H: dbSNP rs2271260.		VAR_043051
	Natural variant	393	1	I → V: dbSNP rs34315917.		VAR_043052
	Natural variant	403	1	S → Y in PFIC1. Ref.7		VAR_043053
	Natural variant	412	1	R → P in PFIC1. Ref.7		VAR_043054
	Natural variant	429	1	E → A: dbSNP rs34018205. Ref.7		VAR_043055
	Natural variant	453	1	S → Y in BRIC1. Ref.7		VAR_043056
	Natural variant	454	1	D → G in BRIC1. Ref.7		VAR_043057
	Natural variant	456	1	T → M in PFIC1. Ref.7		VAR_043058
	Natural variant	500	1	Y → H in PFIC1. Ref.7		VAR_043059
	Natural variant	529	1	Missing in PFIC1. Ref.7		VAR_043060
	Natural variant	535	1	H → L in PFIC1. Ref.7		VAR_043061
	Natural variant	554	1	D → N in PFIC1. Ref.6 Ref.7		VAR_015423
	Natural variant	577	1	I → V: dbSNP rs3745078.		VAR_029272
	Natural variant	580	1	S → N: dbSNP rs33963153.		VAR_043062
	Natural variant	600	1	R → Q in BRIC1; compound heterozygote with N-70. Ref.7		VAR_043063
	Natural variant	600	1	R → W in BRIC1. Ref.7		VAR_043064
	Natural variant	628	1	R → W in BRIC1. Ref.7		VAR_043065
	Natural variant	645 – 699	55	Missing in PFIC1. Ref.1		VAR_008811
	Natural variant	661	1	I → T in BRIC1 and PFIC1; common mutation.		VAR_008812
	Natural variant	674	1	M → T: dbSNP rs35470719.		VAR_043066
	Natural variant	688	1	D → G in PFIC1. Ref.7		VAR_043067
	Natural variant	694	1	I → T in BRIC1. Ref.7		VAR_043068
	Natural variant	733	1	G → R in PFIC1. Ref.7		VAR_043069
	Natural variant	795 – 797	3	Missing in BRIC1. Ref.1		VAR_008814
	Natural variant	814	1	K → N: dbSNP rs34018300.		VAR_043070
	Natural variant	853	1	F → S in PFIC1. Ref.7		VAR_043071
	Natural variant	867	1	R → C in ICP. Ref.9		VAR_043072
	Natural variant	886	1	A → V in a breast cancer sample; somatic mutation. Ref.10		VAR_036499
	Natural variant	892	1	G → R in PFIC1 and BRIC1.		VAR_008813
	Natural variant	952	1	R → Q: dbSNP rs12968116. Ref.8 Ref.9		VAR_029273
	Natural variant	1040	1	G → R in PFIC1. Ref.7		VAR_043073
	Natural variant	1152	1	A → T: dbSNP rs222581. Ref.1 Ref.4		VAR_055045
	Natural variant	1178	1	I → M in a breast cancer sample; somatic mutation. Ref.10		VAR_036500
Experimental info
	Sequence conflict	1016	1	P → L in AAH03534. Ref.4

Sequences

	Sequence		Length	Mass (Da)
	O43520-1 [UniParc]. Last modified May 5, 2009. Version 3. Checksum: 770FEF3946CB579F	FASTA	1,251	143,695
	10 20 30 40 50 60 MSTERDSETT FDEDSQPNDE VVPYSDDETE DELDDQGSAV EPEQNRVNRE AEENREPFRK 70 80 90 100 110 120 ECTWQVKAND RKYHEQPHFM NTKFLCIKES KYANNAIKTY KYNAFTFIPM NLFEQFKRAA 130 140 150 160 170 180 NLYFLALLIL QAVPQISTLA WYTTLVPLLV VLGVTAIKDL VDDVARHKMD KEINNRTCEV 190 200 210 220 230 240 IKDGRFKVAK WKEIQVGDVI RLKKNDFVPA DILLLSSSEP NSLCYVETAE LDGETNLKFK 250 260 270 280 290 300 MSLEITDQYL QREDTLATFD GFIECEEPNN RLDKFTGTLF WRNTSFPLDA DKILLRGCVI 310 320 330 340 350 360 RNTDFCHGLV IFAGADTKIM KNSGKTRFKR TKIDYLMNYM VYTIFVVLIL LSAGLAIGHA 370 380 390 400 410 420 YWEAQVGNSS WYLYDGEDDT PSYRGFLIFW GYIIVLNTMV PISLYVSVEV IRLGQSHFIN 430 440 450 460 470 480 WDLQMYYAEK DTPAKARTTT LNEQLGQIHY IFSDKTGTLT QNIMTFKKCC INGQIYGDHR 490 500 510 520 530 540 DASQHNHNKI EQVDFSWNTY ADGKLAFYDH YLIEQIQSGK EPEVRQFFFL LAVCHTVMVD 550 560 570 580 590 600 RTDGQLNYQA ASPDEGALVN AARNFGFAFL ARTQNTITIS ELGTERTYNV LAILDFNSDR 610 620 630 640 650 660 KRMSIIVRTP EGNIKLYCKG ADTVIYERLH RMNPTKQETQ DALDIFANET LRTLCLCYKE 670 680 690 700 710 720 IEEKEFTEWN KKFMAASVAS TNRDEALDKV YEEIEKDLIL LGATAIEDKL QDGVPETISK 730 740 750 760 770 780 LAKADIKIWV LTGDKKETAE NIGFACELLT EDTTICYGED INSLLHARME NQRNRGGVYA 790 800 810 820 830 840 KFAPPVQESF FPPGGNRALI ITGSWLNEIL LEKKTKRNKI LKLKFPRTEE ERRMRTQSKR 850 860 870 880 890 900 RLEAKKEQRQ KNFVDLACEC SAVICCRVTP KQKAMVVDLV KRYKKAITLA IGDGANDVNM 910 920 930 940 950 960 IKTAHIGVGI SGQEGMQAVM SSDYSFAQFR YLQRLLLVHG RWSYIRMCKF LRYFFYKNFA 970 980 990 1000 1010 1020 FTLVHFWYSF FNGYSAQTAY EDWFITLYNV LYTSLPVLLM GLLDQDVSDK LSLRFPGLYI 1030 1040 1050 1060 1070 1080 VGQRDLLFNY KRFFVSLLHG VLTSMILFFI PLGAYLQTVG QDGEAPSDYQ SFAVTIASAL 1090 1100 1110 1120 1130 1140 VITVNFQIGL DTSYWTFVNA FSIFGSIALY FGIMFDFHSA GIHVLFPSAF QFTGTASNAL 1150 1160 1170 1180 1190 1200 RQPYIWLTII LAVAVCLLPV VAIRFLSMTI WPSESDKIQK HRKRLKAEEQ WQRRQQVFRR 1210 1220 1230 1240 1250 GVSTRRSAYA FSHQRGYADL ISSGRSIRKK RSPLDAIVAD GTAEYRRTGD S

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"A gene encoding a P-type ATPase mutated in two forms of hereditary cholestasis." Bull L.N., van Eijk M.J.T., Pawlikowska L., DeYoung J.A., Juijn J.A., Liao M., Klomp L.W.J., Lomri N., Berger R., Scharschmidt B.F., Knisely A.S., Houwen R.H.J., Freimer N.B. Nat. Genet. 18:219-223(1998) [PubMed: 9500542] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA], VARIANTS PFIC1 SER-288; VAL-308; 645-ILE--ILE-699 DEL AND ARG-892, VARIANTS BRIC1 THR-661 AND 795-GLY--ARG-797 DEL, VARIANT THR-1152. Tissue: Intestine and Liver.
[2]	"DNA sequence and analysis of human chromosome 18." Nusbaum C., Zody M.C., Borowsky M.L., Kamal M., Kodira C.D., Taylor T.D., Whittaker C.A., Chang J.L., Cuomo C.A., Dewar K., FitzGerald M.G., Yang X., Abouelleil A., Allen N.R., Anderson S., Bloom T., Bugalter B., Butler J. , Cook A., DeCaprio D., Engels R., Garber M., Gnirke A., Hafez N., Hall J.L., Norman C.H., Itoh T., Jaffe D.B., Kuroki Y., Lehoczky J., Lui A., Macdonald P., Mauceli E., Mikkelsen T.S., Naylor J.W., Nicol R., Nguyen C., Noguchi H., O'Leary S.B., Piqani B., Smith C.L., Talamas J.A., Topham K., Totoki Y., Toyoda A., Wain H.M., Young S.K., Zeng Q., Zimmer A.R., Fujiyama A., Hattori M., Birren B.W., Sakaki Y., Lander E.S. Nature 437:551-555(2005) [PubMed: 16177791] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[3]	"Multiple members of a third subfamily of P-type ATPases identified by genomic sequences and ESTs." Halleck M.S., Pradhan D., Blackman C.F., Berkes C., Williamson P.L., Schlegel R.A. Genome Res. 8:354-361(1998) [PubMed: 9548971] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] OF 388-661. Tissue: Colon tumor.
[4]	"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] OF 359-1251, VARIANT THR-1152. Tissue: Uterus.
[5]	"Recurrent familial intrahepatic cholestasis in the Faeroe Islands. Phenotypic heterogeneity but genetic homogeneity." Tygstrup N., Steig B.A., Juijn J.A., Bull L.N., Houwen R.H.J. Hepatology 29:506-508(1999) [PubMed: 9918928] [Abstract] Cited for: VARIANT BRIC1 THR-661.
[6]	"A missense mutation in FIC1 is associated with Greenland familial cholestasis." Klomp L.W.J., Bull L.N., Knisely A.S., van Der Doelen M.A., Juijn J.A., Berger R., Forget S., Nielsen I.-M., Eiberg H., Houwen R.H.J. Hepatology 32:1337-1341(2000) [PubMed: 11093741] [Abstract] Cited for: VARIANT PFIC1 ASN-554.
[7]	"Characterization of mutations in ATP8B1 associated with hereditary cholestasis." Klomp L.W.J., Vargas J.C., van Mil S.W.C., Pawlikowska L., Strautnieks S.S., van Eijk M.J.T., Juijn J.A., Pabon-Pena C., Smith L.B., DeYoung J.A., Byrne J.A., Gombert J., van der Brugge G., Berger R., Jankowska I., Pawlowska J., Villa E., Knisely A.S. , Thompson R.J., Freimer N.B., Houwen R.H.J., Bull L.N. Hepatology 40:27-38(2004) [PubMed: 15239083] [Abstract] Cited for: VARIANTS PFIC1 PRO-127; TYR-403; PRO-412; MET-456; HIS-500; PHE-529 DEL; LEU-535; ASN-554; THR-661; GLY-688; ARG-733; SER-853; ARG-892 AND ARG-1040, VARIANTS BRIC1 ASN-70; ASP-308; PHE-344; TYR-453; GLY-454; TRP-600; GLN-600; TRP-628; THR-661; THR-694 AND ARG-892, VARIANT ALA-429.
[8]	"Sequence variation in the ATP8B1 gene and intrahepatic cholestasis of pregnancy." Painter J.N., Savander M., Ropponen A., Nupponen N., Riikonen S., Ylikorkala O., Lehesjoki A.E., Aittomaki K. Eur. J. Hum. Genet. 13:435-439(2005) [PubMed: 15657619] [Abstract] Cited for: VARIANTS ICP THR-45 AND GLU-203, VARIANT GLN-952.
[9]	"ATP8B1 mutations in British cases with intrahepatic cholestasis of pregnancy." Muellenbach R., Bennett A., Tetlow N., Patel N., Hamilton G., Cheng F., Chambers J., Howard R., Taylor-Robinson S.D., Williamson C. Gut 54:829-834(2005) [PubMed: 15888793] [Abstract] Cited for: VARIANT ICP CYS-867, VARIANTS ASN-70; ILE-305 AND GLN-952.
[10]	"The consensus coding sequences of human breast and colorectal cancers." Sjoeblom T., Jones S., Wood L.D., Parsons D.W., Lin J., Barber T.D., Mandelker D., Leary R.J., Ptak J., Silliman N., Szabo S., Buckhaults P., Farrell C., Meeh P., Markowitz S.D., Willis J., Dawson D., Willson J.K.V. , Gazdar A.F., Hartigan J., Wu L., Liu C., Parmigiani G., Park B.H., Bachman K.E., Papadopoulos N., Vogelstein B., Kinzler K.W., Velculescu V.E. Science 314:268-274(2006) [PubMed: 16959974] [Abstract] Cited for: VARIANTS [LARGE SCALE ANALYSIS] VAL-886 AND MET-1178.
+	Additional computationally mapped references.

Web resources

GeneReviews

Cross-references

Sequence databases
EMBLGenBankDDBJ	AF038007 mRNA. Translation: AAC63461.1. AC027097 Genomic DNA. No translation available. AF032442 mRNA. Translation: AAC04328.1. BC003534 mRNA. Translation: AAH03534.1.
IPI	IPI00012851.
RefSeq	NP_005594.1.
UniGene	Hs.216623
3D structure databases
ModBase	Search...
PTM databases
PhosphoSite	O43520.
Proteomic databases
PRIDE	O43520.
Genome annotation databases
Ensembl	ENSG00000081923. Homo sapiens. [Contig view]
GeneID	5205.
KEGG	hsa:5205.
Organism-specific databases
GeneCards	GC18M053466.
HGNC	HGNC:3706. ATP8B1.
MIM	147480. phenotype. 211600. phenotype. 243300. phenotype. 602397. gene.
Orphanet	65682. Benign recurrent intrahepatic cholestasis. 172. Cholestasis, progressive familial intrahepatic. 79306. Cholestasis, progressive familial intrahepatic, type 1. 69665. Intrahepatic cholestasis of pregnancy.
PharmGKB	PA265.
GenAtlas	Search...
Phylogenomic databases
HOGENOM	O43520.
HOVERGEN	O43520.
Enzyme and pathway databases
BRENDA	3.6.3.1. 247.
Gene expression databases
ArrayExpress	O43520.
Bgee	O43520.
CleanEx	HS_ATP8B1.
GermOnline	ENSG00000081923. Homo sapiens.
Family and domain databases
InterPro	IPR008250. ATPase_P-typ_ATPase-assoc-reg. IPR001757. ATPase_P-typ_ion-transptr. IPR018303. ATPase_P-typ_phosphor_site. IPR006539. ATPase_P-typ_Plipid-transl. [Graphical view]
PANTHER	PTHR11939. ATPase_P. 1 hit.
Pfam	PF00122. E1-E2_ATPase. 1 hit. [Graphical view]
PRINTS	PR00119. CATATPASE.
TIGRFAMs	TIGR01652. ATPase-Plipid. 1 hit. TIGR01494. ATPase_P-type. 4 hits.
PROSITE	PS00154. ATPASE_E1_E2. 1 hit. [Graphical view]
ProtoNet	Search...
Other Resources
NextBio	20132.
SOURCE	Search...

Entry information

Entry name

AT8B1_HUMAN

Accession

Primary (citable) accession number: O43520
Secondary accession number(s): Q9BTP8

Entry history

Integrated into UniProtKB/Swiss-Prot:	May 30, 2000
Last sequence update:	May 5, 2009
Last modified:	June 16, 2009
This is version 93 of the entry and version 3 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation project

HPI (Human Proteome Initiative)