ABCD4_HUMAN
ID ABCD4_HUMAN Reviewed; 606 AA.
AC O14678; A8K5L7; Q6IAQ0; Q96E75;
DT 30-MAY-2000, integrated into UniProtKB/Swiss-Prot.
DT 01-JAN-1998, sequence version 1.
DT 03-AUG-2022, entry version 188.
DE RecName: Full=Lysosomal cobalamin transporter ABCD4 {ECO:0000305|PubMed:27456980};
DE EC=7.6.2.8 {ECO:0000269|PubMed:33845046, ECO:0000305|PubMed:28572511, ECO:0000305|PubMed:31467407};
DE AltName: Full=ATP-binding cassette sub-family D member 4 {ECO:0000312|HGNC:HGNC:68};
DE AltName: Full=PMP70-related protein;
DE Short=P70R;
DE AltName: Full=Peroxisomal membrane protein 1-like;
DE Short=PXMP1-L;
DE AltName: Full=Peroxisomal membrane protein 69;
DE Short=PMP69;
GN Name=ABCD4 {ECO:0000312|HGNC:HGNC:68}; Synonyms=PXMP1L;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA].
RX PubMed=9266848; DOI=10.1006/bbrc.1997.7102;
RA Holzinger A., Kammerer S., Roscher A.A.;
RT "Primary structure of human PMP69, a putative peroxisomal ABC-
RT transporter.";
RL Biochem. Biophys. Res. Commun. 237:152-157(1997).
RN [2]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA / MRNA].
RX PubMed=9599016; DOI=10.1016/s0014-5793(98)00354-8;
RA Holzinger A., Roscher A.A., Landgraf P., Lichtner P., Kammerer S.;
RT "Genomic organization and chromosomal localization of the human peroxisomal
RT membrane protein-1-like protein (PXMP1-L) gene encoding a peroxisomal ABC
RT transporter.";
RL FEBS Lett. 426:238-242(1998).
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA].
RX PubMed=9302272; DOI=10.1093/hmg/6.11.1925;
RA Shani N., Jimenez-Sanchez G., Steel G., Dean M., Valle D.;
RT "Identification of a fourth half ABC transporter in the human peroxisomal
RT membrane.";
RL Hum. Mol. Genet. 6:1925-1931(1997).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA], AND VARIANTS THR-304 AND LYS-368.
RA Kalnine N., Chen X., Rolfs A., Halleck A., Hines L., Eisenstein S.,
RA Koundinya M., Raphael J., Moreira D., Kelley T., LaBaer J., Lin Y.,
RA Phelan M., Farmer A.;
RT "Cloning of human full-length CDSs in BD Creator(TM) system donor vector.";
RL Submitted (MAY-2003) to the EMBL/GenBank/DDBJ databases.
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Tongue;
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H.,
RA Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M.,
RA Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K.,
RA Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T.,
RA Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M.,
RA Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S.,
RA Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H.,
RA Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K.,
RA Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N.,
RA Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y.,
RA Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K.,
RA Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T.,
RA Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T.,
RA Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y.,
RA Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H.,
RA Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y.,
RA Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H.,
RA Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O.,
RA Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [6]
RP FUNCTION, INTERACTION WITH LMBRD1 AND MMACHC, AND SUBCELLULAR LOCATION.
RX PubMed=25535791; DOI=10.3109/09687688.2014.990998;
RA Deme J.C., Hancock M.A., Xia X., Shintre C.A., Plesa M., Kim J.C.,
RA Carpenter E.P., Rosenblatt D.S., Coulton J.W.;
RT "Purification and interaction analyses of two human lysosomal vitamin B12
RT transporters: LMBD1 and ABCD4.";
RL Mol. Membr. Biol. 31:250-261(2014).
RN [7]
RP FUNCTION, SUBCELLULAR LOCATION, AND INTERACTION WITH LMBRD1.
RX PubMed=27456980; DOI=10.1038/srep30183;
RA Kawaguchi K., Okamoto T., Morita M., Imanaka T.;
RT "Translocation of the ABC transporter ABCD4 from the endoplasmic reticulum
RT to lysosomes requires the escort protein LMBD1.";
RL Sci. Rep. 6:30183-30183(2016).
RN [8]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA], AND VARIANTS THR-304 AND LYS-368.
RA Ebert L., Schick M., Neubert P., Schatten R., Henze S., Korn B.;
RT "Cloning of human full open reading frames in Gateway(TM) system entry
RT vector (pDONR201).";
RL Submitted (JUN-2004) to the EMBL/GenBank/DDBJ databases.
RN [9]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA], AND VARIANTS THR-304 AND LYS-368.
RC TISSUE=Muscle;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA project:
RT the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [10]
RP FUNCTION, VARIANT MAHCJ CYS-319, INVOLVEMENT IN MAHCJ, MUTAGENESIS OF
RP LYS-427; ASP-548 AND GLU-549, AND SUBCELLULAR LOCATION.
RX PubMed=22922874; DOI=10.1038/ng.2386;
RA Coelho D., Kim J.C., Miousse I.R., Fung S., du Moulin M., Buers I.,
RA Suormala T., Burda P., Frapolli M., Stucki M., Nurnberg P., Thiele H.,
RA Robenek H., Hohne W., Longo N., Pasquali M., Mengel E., Watkins D.,
RA Shoubridge E.A., Majewski J., Rosenblatt D.S., Fowler B., Rutsch F.,
RA Baumgartner M.R.;
RT "Mutations in ABCD4 cause a new inborn error of vitamin B12 metabolism.";
RL Nat. Genet. 44:1152-1155(2012).
RN [11]
RP INVOLVEMENT IN MAHCJ, VARIANT MAHCJ GLN-432, CHARACTERIZATION OF VARIANTS
RP MAHCJ LYS-141 AND GLN-432, SUBCELLULAR LOCATION, INTERACTION WITH LMBRD1,
RP MUTAGENESIS OF GLY-426; LYS-427 AND ASP-548, FUNCTION, AND CATALYTIC
RP ACTIVITY.
RX PubMed=28572511; DOI=10.1074/jbc.m117.784819;
RA Fettelschoss V., Burda P., Sagne C., Coelho D., De Laet C., Lutz S.,
RA Suormala T., Fowler B., Pietrancosta N., Gasnier B., Bornhauser B.,
RA Froese D.S., Baumgartner M.R.;
RT "Clinical or ATPase domain mutations in ABCD4 disrupt the interaction
RT between the vitamin B12-trafficking proteins ABCD4 and LMBD1.";
RL J. Biol. Chem. 292:11980-11991(2017).
RN [12]
RP CATALYTIC ACTIVITY, FUNCTION, BIOPHYSICOCHEMICAL PROPERTIES, MUTAGENESIS OF
RP ASN-141; TYR-319 AND LYS-427, SUBCELLULAR LOCATION, INTERACTION WITH
RP LMBRD1, CHARACTERIZATION OF VARIANTS MAHCJ CYS-319 AND ASN-141, AND
RP SUBUNIT.
RX PubMed=33845046; DOI=10.1016/j.jbc.2021.100654;
RA Kitai K., Kawaguchi K., Tomohiro T., Morita M., So T., Imanaka T.;
RT "The lysosomal protein ABCD4 can transport vitamin B12 across liposomal
RT membranes in vitro.";
RL J. Biol. Chem. 296:100654-100654(2021).
RN [13]
RP VARIANTS THR-304 AND LYS-368.
RX PubMed=12111378; DOI=10.1007/s100380200041;
RA Iida A., Saito S., Sekine A., Mishima C., Kitamura Y., Kondo K.,
RA Harigae S., Osawa S., Nakamura Y.;
RT "Catalog of 605 single-nucleotide polymorphisms (SNPs) among 13 genes
RT encoding human ATP-binding cassette transporters: ABCA4, ABCA7, ABCA8,
RT ABCD1, ABCD3, ABCD4, ABCE1, ABCF1, ABCG1, ABCG2, ABCG4, ABCG5, and ABCG8.";
RL J. Hum. Genet. 47:285-310(2002).
RN [14]
RP VARIANT MAHCJ LYS-141, AND INVOLVEMENT IN MAHCJ.
RX PubMed=23141461; DOI=10.1016/j.ymgme.2012.10.005;
RA Kim J.C., Lee N.C., Hwu P.W., Chien Y.H., Fahiminiya S., Majewski J.,
RA Watkins D., Rosenblatt D.S.;
RT "Late onset of symptoms in an atypical patient with the cblJ inborn error
RT of vitamin B12 metabolism: diagnosis and novel mutation revealed by exome
RT sequencing.";
RL Mol. Genet. Metab. 107:664-668(2012).
RN [15] {ECO:0007744|PDB:6JBJ}
RP STRUCTURE BY ELECTRON MICROSCOPY (3.60 ANGSTROMS) OF 2-606,
RP CHARACTERIZATION OF VARIANTS MAHCJ CYS-319 AND GLN-432, MUTAGENESIS OF
RP GLU-549, FUNCTION, CATALYTIC ACTIVITY, AND BIOPHYSICOCHEMICAL PROPERTIES.
RX PubMed=31467407; DOI=10.1038/s41422-019-0222-z;
RA Xu D., Feng Z., Hou W.T., Jiang Y.L., Wang L., Sun L., Zhou C.Z., Chen Y.;
RT "Cryo-EM structure of human lysosomal cobalamin exporter ABCD4.";
RL Cell Res. 29:1039-1041(2019).
CC -!- FUNCTION: Lysosomal membrane protein that transports cobalamin (Vitamin
CC B12) from the lysosomal lumen to the cytosol in an ATP-dependent manner
CC (PubMed:22922874,PubMed:33845046,PubMed:28572511,PubMed:31467407).
CC Targeted by LMBRD1 lysosomal chaperone from the endoplasmic reticulum
CC to the lysosomal membrane (PubMed:27456980). Then forms a complex with
CC lysosomal chaperone LMBRD1 and cytosolic MMACHC to transport cobalamin
CC across the lysosomal membrane (PubMed:25535791).
CC {ECO:0000269|PubMed:22922874, ECO:0000269|PubMed:27456980,
CC ECO:0000269|PubMed:28572511, ECO:0000269|PubMed:31467407,
CC ECO:0000269|PubMed:33845046, ECO:0000303|PubMed:25535791}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=an R-cob(III)alamin(out) + ATP + H2O = ADP + an R-
CC cob(III)alamin(in) + H(+) + phosphate; Xref=Rhea:RHEA:17873,
CC ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, ChEBI:CHEBI:30616,
CC ChEBI:CHEBI:43474, ChEBI:CHEBI:140785, ChEBI:CHEBI:456216;
CC EC=7.6.2.8; Evidence={ECO:0000269|PubMed:33845046,
CC ECO:0000305|PubMed:28572511, ECO:0000305|PubMed:31467407};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:17874;
CC Evidence={ECO:0000305|PubMed:33845046};
CC -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC Kinetic parameters:
CC KM=426 uM for cobalamin {ECO:0000269|PubMed:33845046};
CC Vmax=667 pmol/min/mg enzyme toward cobalamin
CC {ECO:0000269|PubMed:33845046};
CC Vmax=11.8 nmol/min/mg enzyme toward ATP
CC {ECO:0000269|PubMed:31467407};
CC -!- SUBUNIT: Homodimer or heterodimer (PubMed:27456980,PubMed:33845046).
CC Interacts with LMBRD1; this interaction induces the translocation of
CC ABCD4 from the ER to the lysosome membrane
CC (PubMed:27456980,PubMed:28572511). Interacts with LMBRD1 and MMACHC;
CC this interaction ensures the transport of cobalamin from the lysosome
CC to the cytosol (PubMed:25535791). {ECO:0000269|PubMed:25535791,
CC ECO:0000269|PubMed:27456980, ECO:0000269|PubMed:33845046}.
CC -!- INTERACTION:
CC O14678; O14678: ABCD4; NbExp=2; IntAct=EBI-714396, EBI-714396;
CC O14678; Q9NUN5: LMBRD1; NbExp=7; IntAct=EBI-714396, EBI-2805231;
CC -!- SUBCELLULAR LOCATION: Endoplasmic reticulum membrane
CC {ECO:0000269|PubMed:27456980}; Multi-pass membrane protein
CC {ECO:0000255}. Lysosome membrane {ECO:0000269|PubMed:22922874,
CC ECO:0000269|PubMed:25535791, ECO:0000269|PubMed:27456980,
CC ECO:0000269|PubMed:28572511, ECO:0000269|PubMed:33845046}; Multi-pass
CC membrane protein {ECO:0000255}. Note=Targeted by LMBRD1 lysosomal
CC chaperone to the lysosomal membrane. {ECO:0000269|PubMed:27456980,
CC ECO:0000269|PubMed:28572511}.
CC -!- TISSUE SPECIFICITY: Ubiquitous.
CC -!- DISEASE: Methylmalonic aciduria and homocystinuria type cblJ (MAHCJ)
CC [MIM:614857]: A disorder of cobalamin metabolism characterized by
CC decreased levels of the coenzymes adenosylcobalamin (AdoCbl) and
CC methylcobalamin (MeCbl). Clinical features include feeding
CC difficulties, poor growth, hypotonia, lethargy, anemia, and
CC developmental delay. {ECO:0000269|PubMed:22922874,
CC ECO:0000269|PubMed:23141461, ECO:0000269|PubMed:28572511,
CC ECO:0000269|PubMed:31467407, ECO:0000269|PubMed:33845046}. Note=The
CC disease is caused by variants affecting the gene represented in this
CC entry.
CC -!- SIMILARITY: Belongs to the ABC transporter superfamily. ABCD family.
CC Peroxisomal fatty acyl CoA transporter (TC 3.A.1.203) subfamily.
CC {ECO:0000305}.
CC -!- CAUTION: Originally proposed to be a peroxisomal protein
CC (PubMed:9266848). Recent studies have suggested its localization to the
CC endoplasmic reticulum and within the lysosome (PubMed:27456980).
CC {ECO:0000269|PubMed:27456980, ECO:0000269|PubMed:28572511,
CC ECO:0000269|PubMed:33845046, ECO:0000269|PubMed:9266848}.
CC -!- WEB RESOURCE: Name=ABCMdb; Note=Database for mutations in ABC proteins;
CC URL="http://abcm2.hegelab.org/search";
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DR EMBL; Y14318; CAA74699.1; -; Genomic_DNA.
DR EMBL; Y14319; CAA74699.1; JOINED; Genomic_DNA.
DR EMBL; Y14320; CAA74699.1; JOINED; Genomic_DNA.
DR EMBL; Y14321; CAA74699.1; JOINED; Genomic_DNA.
DR EMBL; Y14322; CAA74699.1; JOINED; Genomic_DNA.
DR EMBL; Y14323; CAA74699.1; JOINED; Genomic_DNA.
DR EMBL; AF009746; AAB83967.1; -; mRNA.
DR EMBL; BT007412; AAP36080.1; -; mRNA.
DR EMBL; AK291332; BAF84021.1; -; mRNA.
DR EMBL; CR457104; CAG33385.1; -; mRNA.
DR EMBL; BC012815; AAH12815.1; -; mRNA.
DR CCDS; CCDS9828.1; -.
DR PIR; JC5604; JC5604.
DR RefSeq; NP_005041.1; NM_005050.3.
DR PDB; 6JBJ; EM; 3.60 A; A/B=2-606.
DR PDBsum; 6JBJ; -.
DR AlphaFoldDB; O14678; -.
DR SMR; O14678; -.
DR BioGRID; 111784; 39.
DR IntAct; O14678; 17.
DR STRING; 9606.ENSP00000349396; -.
DR TCDB; 3.A.1.203.9; the atp-binding cassette (abc) superfamily.
DR iPTMnet; O14678; -.
DR PhosphoSitePlus; O14678; -.
DR BioMuta; ABCD4; -.
DR EPD; O14678; -.
DR jPOST; O14678; -.
DR MassIVE; O14678; -.
DR MaxQB; O14678; -.
DR PaxDb; O14678; -.
DR PeptideAtlas; O14678; -.
DR PRIDE; O14678; -.
DR ProteomicsDB; 48163; -.
DR Antibodypedia; 184; 243 antibodies from 30 providers.
DR DNASU; 5826; -.
DR Ensembl; ENST00000356924.9; ENSP00000349396.4; ENSG00000119688.21.
DR GeneID; 5826; -.
DR KEGG; hsa:5826; -.
DR MANE-Select; ENST00000356924.9; ENSP00000349396.4; NM_005050.4; NP_005041.1.
DR UCSC; uc001xpr.3; human.
DR CTD; 5826; -.
DR DisGeNET; 5826; -.
DR GeneCards; ABCD4; -.
DR GeneReviews; ABCD4; -.
DR HGNC; HGNC:68; ABCD4.
DR HPA; ENSG00000119688; Low tissue specificity.
DR MalaCards; ABCD4; -.
DR MIM; 603214; gene.
DR MIM; 614857; phenotype.
DR neXtProt; NX_O14678; -.
DR OpenTargets; ENSG00000119688; -.
DR Orphanet; 369955; Methylmalonic acidemia with homocystinuria, type cblJ.
DR PharmGKB; PA24403; -.
DR VEuPathDB; HostDB:ENSG00000119688; -.
DR eggNOG; KOG0060; Eukaryota.
DR GeneTree; ENSGT00950000182955; -.
DR HOGENOM; CLU_007587_7_0_1; -.
DR InParanoid; O14678; -.
DR OMA; RFWISAR; -.
DR OrthoDB; 309052at2759; -.
DR PhylomeDB; O14678; -.
DR TreeFam; TF105205; -.
DR BRENDA; 7.6.2.8; 2681.
DR PathwayCommons; O14678; -.
DR Reactome; R-HSA-5683329; Defective ABCD4 causes MAHCJ.
DR Reactome; R-HSA-9758881; Uptake of dietary cobalamins into enterocytes.
DR Reactome; R-HSA-9758890; Transport of RCbl within the body.
DR SignaLink; O14678; -.
DR BioGRID-ORCS; 5826; 27 hits in 1075 CRISPR screens.
DR ChiTaRS; ABCD4; human.
DR GeneWiki; ABCD4; -.
DR GenomeRNAi; 5826; -.
DR Pharos; O14678; Tbio.
DR PRO; PR:O14678; -.
DR Proteomes; UP000005640; Chromosome 14.
DR RNAct; O14678; protein.
DR Bgee; ENSG00000119688; Expressed in right uterine tube and 176 other tissues.
DR ExpressionAtlas; O14678; baseline and differential.
DR Genevisible; O14678; HS.
DR GO; GO:0043190; C:ATP-binding cassette (ABC) transporter complex; NAS:UniProtKB.
DR GO; GO:0005789; C:endoplasmic reticulum membrane; IDA:UniProtKB.
DR GO; GO:0016021; C:integral component of membrane; NAS:UniProtKB.
DR GO; GO:0005765; C:lysosomal membrane; IDA:UniProtKB.
DR GO; GO:0005778; C:peroxisomal membrane; IBA:GO_Central.
DR GO; GO:0005777; C:peroxisome; IDA:UniProtKB.
DR GO; GO:0015420; F:ABC-type vitamin B12 transporter activity; IDA:MGI.
DR GO; GO:0005524; F:ATP binding; IBA:GO_Central.
DR GO; GO:0042626; F:ATPase-coupled transmembrane transporter activity; IBA:GO_Central.
DR GO; GO:0042802; F:identical protein binding; IPI:IntAct.
DR GO; GO:0005324; F:long-chain fatty acid transporter activity; IBA:GO_Central.
DR GO; GO:1990830; P:cellular response to leukemia inhibitory factor; IEA:Ensembl.
DR GO; GO:0009235; P:cobalamin metabolic process; IDA:MGI.
DR GO; GO:0015889; P:cobalamin transport; IMP:UniProtKB.
DR GO; GO:0006635; P:fatty acid beta-oxidation; IBA:GO_Central.
DR GO; GO:0015910; P:long-chain fatty acid import into peroxisome; IBA:GO_Central.
DR GO; GO:0007031; P:peroxisome organization; IBA:GO_Central.
DR GO; GO:0055085; P:transmembrane transport; NAS:UniProtKB.
DR GO; GO:0042760; P:very long-chain fatty acid catabolic process; IBA:GO_Central.
DR Gene3D; 1.20.1560.10; -; 1.
DR Gene3D; 3.40.50.300; -; 1.
DR InterPro; IPR003593; AAA+_ATPase.
DR InterPro; IPR011527; ABC1_TM_dom.
DR InterPro; IPR036640; ABC1_TM_sf.
DR InterPro; IPR003439; ABC_transporter-like_ATP-bd.
DR InterPro; IPR017871; ABC_transporter-like_CS.
DR InterPro; IPR027417; P-loop_NTPase.
DR Pfam; PF06472; ABC_membrane_2; 1.
DR Pfam; PF00005; ABC_tran; 1.
DR SMART; SM00382; AAA; 1.
DR SUPFAM; SSF52540; SSF52540; 1.
DR SUPFAM; SSF90123; SSF90123; 1.
DR PROSITE; PS50929; ABC_TM1F; 1.
DR PROSITE; PS00211; ABC_TRANSPORTER_1; 1.
DR PROSITE; PS50893; ABC_TRANSPORTER_2; 1.
PE 1: Evidence at protein level;
KW 3D-structure; ATP-binding; Disease variant; Endoplasmic reticulum;
KW Lysosome; Membrane; Nucleotide-binding; Reference proteome; Translocase;
KW Transmembrane; Transmembrane helix; Transport.
FT CHAIN 1..606
FT /note="Lysosomal cobalamin transporter ABCD4"
FT /id="PRO_0000093312"
FT TRANSMEM 43..63
FT /note="Helical"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00441"
FT TRANSMEM 76..96
FT /note="Helical"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00441"
FT TRANSMEM 190..210
FT /note="Helical"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00441"
FT TRANSMEM 279..299
FT /note="Helical"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00441"
FT TRANSMEM 314..334
FT /note="Helical"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00441"
FT DOMAIN 39..332
FT /note="ABC transmembrane type-1"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00441"
FT DOMAIN 389..603
FT /note="ABC transporter"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00434"
FT BINDING 421..428
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00434"
FT VARIANT 141
FT /note="N -> K (in MAHCJ; does not affect ATPase activity.
FT Loss of cobalamin transport activity. Decreases interaction
FT with LMBD1. Does not affect lysosomal subcellular location;
FT dbSNP:rs776529140)"
FT /evidence="ECO:0000269|PubMed:23141461,
FT ECO:0000269|PubMed:28572511, ECO:0000269|PubMed:33845046"
FT /id="VAR_084972"
FT VARIANT 172
FT /note="V -> I (in dbSNP:rs34992370)"
FT /id="VAR_048134"
FT VARIANT 304
FT /note="A -> T (in dbSNP:rs4148077)"
FT /evidence="ECO:0000269|PubMed:12111378,
FT ECO:0000269|PubMed:15489334, ECO:0000269|Ref.4,
FT ECO:0000269|Ref.8"
FT /id="VAR_020778"
FT VARIANT 319
FT /note="Y -> C (in MAHCJ; strong decrease of ATPase
FT activity. Strong decrease of cobalamin transport activity;
FT dbSNP:rs201777056)"
FT /evidence="ECO:0000269|PubMed:22922874,
FT ECO:0000269|PubMed:31467407, ECO:0000269|PubMed:33845046"
FT /id="VAR_069097"
FT VARIANT 350
FT /note="T -> R (in dbSNP:rs35073715)"
FT /id="VAR_048135"
FT VARIANT 368
FT /note="E -> K (in dbSNP:rs3742801)"
FT /evidence="ECO:0000269|PubMed:12111378,
FT ECO:0000269|PubMed:15489334, ECO:0000269|Ref.4,
FT ECO:0000269|Ref.8"
FT /id="VAR_020222"
FT VARIANT 432
FT /note="R -> Q (in MAHCJ; decreases interaction with LMBD1.
FT Does not affect lysosomal subcellular location. Decreases
FT ATPase activity; dbSNP:rs745414252)"
FT /evidence="ECO:0000269|PubMed:28572511,
FT ECO:0000269|PubMed:31467407"
FT /id="VAR_084973"
FT MUTAGEN 141
FT /note="N->A,D: Does not affect ATPase nor cobalamin
FT transport activities."
FT /evidence="ECO:0000269|PubMed:33845046"
FT MUTAGEN 319
FT /note="Y->A: Decreases of ATPase activity. Decreases
FT cobalamin transport activity."
FT /evidence="ECO:0000269|PubMed:33845046"
FT MUTAGEN 319
FT /note="Y->F: Does not affect ATPase activity. Does not
FT affect cobalamin transport activity."
FT /evidence="ECO:0000269|PubMed:33845046"
FT MUTAGEN 426
FT /note="G->A: Decreases interaction with LMBD1. Decreases
FT colocalization with LMBD1. Decreases cobalamin transport
FT activity."
FT /evidence="ECO:0000269|PubMed:28572511"
FT MUTAGEN 427
FT /note="K->A: Loss of ATPase activity. Loss of cobalamin
FT transport activity."
FT /evidence="ECO:0000269|PubMed:33845046"
FT MUTAGEN 427
FT /note="K->L: Decreases interaction with LMBD1. Decreases
FT colocalization with LMBD1. Decreases cobalamin transport
FT activity. Reduces synthesis of adenosylcobalamin and
FT methylcobalamin."
FT /evidence="ECO:0000269|PubMed:22922874,
FT ECO:0000269|PubMed:28572511"
FT MUTAGEN 548
FT /note="D->N: Decreases interaction with LMBD1. Reduces
FT synthesis of adenosylcobalamin and methylcobalamin."
FT /evidence="ECO:0000269|PubMed:22922874,
FT ECO:0000269|PubMed:28572511"
FT MUTAGEN 549
FT /note="E->Q: Decreases ATPase activity. Reduces synthesis
FT of adenosylcobalamin and methylcobalamin."
FT /evidence="ECO:0000269|PubMed:22922874,
FT ECO:0000269|PubMed:31467407"
FT CONFLICT 594
FT /note="G -> V (in Ref. 5; BAF84021)"
FT /evidence="ECO:0000305"
FT CONFLICT 606
FT /note="E -> D (in Ref. 8; CAG33385)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 606 AA; 68597 MW; 2D88DEFED0EA0777 CRC64;
MAVAGPAPGA GARPRLDLQF LQRFLQILKV LFPSWSSQNA LMFLTLLCLT LLEQFVIYQV
GLIPSQYYGV LGNKDLEGFK TLTFLAVMLI VLNSTLKSFD QFTCNLLYVS WRKDLTEHLH
RLYFRGRAYY TLNVLRDDID NPDQRISQDV ERFCRQLSSM ASKLIISPFT LVYYTYQCFQ
STGWLGPVSI FGYFILGTVV NKTLMGPIVM KLVHQEKLEG DFRFKHMQIR VNAEPAAFYR
AGHVEHMRTD RRLQRLLQTQ RELMSKELWL YIGINTFDYL GSILSYVVIA IPIFSGVYGD
LSPAELSTLV SKNAFVCIYL ISCFTQLIDL STTLSDVAGY THRIGQLRET LLDMSLKSQD
CEILGESEWG LDTPPGWPAA EPADTAFLLE RVSISAPSSD KPLIKDLSLK ISEGQSLLIT
GNTGTGKTSL LRVLGGLWTS TRGSVQMLTD FGPHGVLFLP QKPFFTDGTL REQVIYPLKE
VYPDSGSADD ERILRFLELA GLSNLVARTE GLDQQVDWNW YDVLSPGEMQ RLSFARLFYL
QPKYAVLDEA TSALTEEVES ELYRIGQQLG MTFISVGHRQ SLEKFHSLVL KLCGGGRWEL
MRIKVE
