Human ABCD4 / cblJ complementation group. ATP-binding cassette sub-family D member 4,
also historically PMP69 / P70R / PXMP1-L. HGNC:68. Chromosome 14q24.3, 606 aa.
Molecular function: ATP-dependent lysosomal cobalamin (vitamin B12) exporter.
ABC transporter that hydrolyzes ATP and translocates cobalamin across the lysosomal
membrane. EC 7.6.2.8; Rhea RHEA:17873 (R-cob(III)alamin(out) + ATP + H2O =
R-cob(III)alamin(in) + ADP + Pi + H+). Km 426 uM cobalamin, Vmax 667 pmol/min/mg
PMID:33845046. Reconstituted purified ABCD4 in liposomes transported cobalamin
from inside to outside in an ATPase-dependent manner; the Walker A K427A mutant lost
both ATPase and transport activity PMID:33845046. GOA current MF term:
GO:0015420 "ABC-type vitamin B12 transporter activity" (EXP/IDA/IMP, PMID:33845046).
Biological process: cobalamin transport (GO:0015889) / cobalamin metabolic
process (GO:0009235). After transcobalamin-bound cobalamin is endocytosed and
degraded in the lysosome, ABCD4 exports free cobalamin to the cytosol where MMACHC
processes it into methylcobalamin (methionine synthase cofactor) and
adenosylcobalamin (methylmalonyl-CoA mutase cofactor) [PMID:33845046, PMID:27456980].
Localization: Lysosomal membrane (GO:0005765), multi-pass. Also ER membrane
(GO:0005789) as biosynthetic intermediate — ABCD4 lacks its own peroxisomal
targeting signal (no NH2-terminal hydrophilic region), is co-translationally
inserted into the ER, and requires the escort protein LMBD1 (LMBRD1, Q9NUN5) to
translocate to the lysosomal membrane [PMID:27456980, PMID:19010322, PMID:28572511].
NOT peroxisomal — original peroxisomal assignment (PMID:9266848, PMID:9302272,
PMID:14533738) was overturned; UniProt CAUTION note documents this. NOT|located_in
peroxisome is experimentally supported [PMID:19010322, PMID:27456980].
Interactions: LMBD1/LMBRD1 (Q9NUN5) escort/complex partner (functional, well
supported); MMACHC (cytosolic B12 processing) forms trafficking complex
PMID:25535791. Homodimer (self, O14678). High-throughput interactome hits:
FAM234B (A2RU67), LMBRD1, self — from proteome-scale screens (PMID:28514442,
PMID:33961781, PMID:40205054); these are bare "protein binding" and non-informative.
Disease: Methylmalonic aciduria and homocystinuria type cblJ (MAHCJ, MIM:614857).
Failure to release cobalamin from lysosomes; decreased AdoCbl and MeCbl
[PMID:22922874, PMID:23141461, PMID:28572511].
Peroxisomal/fatty-acid IBA cluster (GO:0005778 peroxisomal membrane; GO:0005324
long-chain FA transmembrane transporter; GO:0006635 FA beta-oxidation; GO:0015910
LCFA import into peroxisome; GO:0042760 VLCFA catabolic process; GO:0007031
peroxisome organization) are propagated from peroxisomal ABCD1-3 paralogs and are
contradicted by ABCD4's demonstrated lysosomal localization and cobalamin (not fatty
acid) substrate. These are wrong for ABCD4 -> REMOVE (IBA over-propagation, arguable
on biological grounds per curation policy). GO:0005777 peroxisome IDA (PMID:14533738,
PMID:9302272) reflects the superseded early assignment; the NOT|peroxisome IDAs and
UniProt CAUTION overrule them.
Core: GO:0015420 (MF) + GO:0015889 cobalamin transport / GO:0009235 cobalamin
metabolic process (BP) + GO:0005765 lysosomal membrane (CC); ATP binding / ATP
hydrolysis secondary.
Deep research: falcon out of credits (HTTP 402); grounded in UniProt + GOA + cached PMIDs.
Re-read all 51 annotation rows against the UniProt record, all cited primary abstracts, the full localization/transport papers (PMID:27456980 and PMID:33845046), and the five cached Reactome events. Traced the challenged inherited functions to PTHR11384/PTN004256010. Broad membrane, transport and ABC transporter assertions are true core properties and were restored; no donor-count objection is used.
Direct ER sorting and negative peroxisome localization justify rejecting native peroxisomal location/import, but they do not separately refute all lipid metabolism or peroxisome-organization processes. Those independent claims remain UNDECIDED pending the coordinated hypothesis report. PMID:14533738 explicitly reports GFP-labelled human PMP69 fragments targeting peroxisomes, so that positive experimental row is UNDECIDED for construct-context reconciliation, not dismissed because the title emphasizes ABCD1. The earlier general native peroxisome assignment from PMID:9302272 remains rejected in light of direct later contradictory localization, while its rat-antibody versus human-full-length experimental context is explicitly acknowledged.
Evidence excerpts: PMID:27456980, "ABCD4 does not localize to peroxisomes"; PMID:19010322, "only P70R lacks the region and is translated with NH(2)-terminal hydrophobic TMS1."; PMID:33845046, "ABCD4 transports cobalamin from the inside to the outside of liposomes in a manner that is dependent on ATPase activity". The description now identifies the specific N-terminal targeting difference rather than claiming absence of every organelle-targeting signal.