ABCC4 (MRP4) — curation notes

UniProt: O15439 (MRP4_HUMAN). HGNC symbol ABCC4. ATP-binding cassette sub-family C member 4,
also "multidrug resistance-associated protein 4" / "MOAT-B". 1325 aa, polytopic membrane protein.

Architecture (UniProt O15439)

• Multi-pass (polytopic) membrane protein with two transmembrane domains and two
  cytoplasmic nucleotide-binding (ABC transporter) domains
  [file:human/ABCC4/ABCC4-uniprot.txt FT DOMAIN 93..377, 410..633, 711..1005, 1041..1274;
  12 predicted transmembrane helices].
• "The two ABC transporter domains, also known as nucleotide-binding domains, are essential
  for ATP binding and hydrolysis" (PMID:38886124, PMID:40138312, cryo-EM; UniProt DOMAIN).
• C-terminal class-I PDZ-binding motif [file:human/ABCC4/ABCC4-uniprot.txt FT MOTIF 1322..1325].
  Cryo-EM shows MRP4 is a monomer (PMID:38886124, PMID:40138312).
• EC numbers assigned: 7.6.2.2 (xenobiotic), 7.6.2.3 (glutathione S-conjugate), plus 7.6.2.-.

Core molecular function: ATP-driven organic-anion efflux

MRP4 is a primary active (ATP-dependent) efflux pump for a broad spectrum of organic anions.
ATPase activity is direct: PMID:15364914 and is stimulated by
transported substrates PMID:15364914.

Substrate classes with experimental support:

• Cyclic nucleotides (cAMP, cGMP). Apical renal efflux pump for urinary cAMP/cGMP
  PMID:11856762;
  PMID:15454390. cGMP transport is
  positive-cooperative (Km ~180 µM) and modulated by urate.
• Prostaglandins (PGE1, PGE2). PMID:25173977;
  KM 2.1 µM (PGE1), 3.4 µM (PGE2) (UniProt BIOPHYSICOCHEMICAL PROPERTIES). NSAIDs inhibit transport.
• Glutathione and GSH S-conjugates / leukotrienes. PMID:17959747 and
  PMID:17959747 (LTC4 KM 0.13 µM;
  GSH not required for LTC4). Interacts with GSH conjugates such as
  PMID:11856762.
• Bile acids (cotransport with GSH). PMID:16282361;
  PMID:12883481. Proposed basolateral/sinusoidal overflow pathway
  for bile acids and a source of plasma GSH.
• Urate. PMID:15454390; candidate apical pump for urinary urate excretion.
• Steroid conjugates. DHEA-3-sulfate, testosterone-17-sulfate, estradiol-17/estriol-16-glucuronide
  (UniProt CATALYTIC ACTIVITY; PMID:29175180, PMID:39993711); no transport of estrone 3-sulfate.
• Xenobiotics / drugs. Ganciclovir PMID:12105214, 6-MP and PMEA PMID:18300232, cephalosporins PMID:17344354, methotrexate/folate (PMID:11856762, low
  affinity). This underlies its multidrug-resistance phenotype.

Localization

Tissue-dependent polarity: apical in kidney proximal tubule
PMID:11856762, basolateral
in hepatocytes (PMID:12883481). Present at blood-tissue barriers (blood-brain, blood-CSF, blood-testis;
PMID:18619525, PMID:23137377, PMID:24130369, PMID:25986174, PMID:26590417, PMID:30280653) and in
platelet dense-granule membranes PMID:15297306, where it loads cyclic nucleotides/nucleotides for mediator
storage. UniProt: "Its localization to the basolateral or apical membranes is tissue-dependent."

PDZ interactome (protein-binding annotations)

The ~37 GO:0005515 protein binding GOA rows all report interactions with PDZ-domain-containing
proteins (SNX27, PDZK1, NHERF2/4, DLG1/2/4/5, MAGI1-3, SCRIB, TJP1-3, PARD3/3B, PATJ, MPP1, GRIP1/2,
syntenin, whirlin, harmonin/USH1C, etc.) via MRP4's C-terminal PDZ-binding motif. These were reviewed
as MODIFY → GO:0030165 PDZ domain binding rather than bare "protein binding".
PMID:22411990 — SNX27 accelerates MRP4 internalization;
PMID:29146910 — MPP1
enhances MRP4 surface expression/drug resistance in AML;
PMID:36115835 —
large-scale PDZ-PBM affinity map; PMID:24550280 — Scribble PDZ phage-display screen. These PDZ
interactions govern MRP4 trafficking, turnover and polarized membrane targeting.

Downstream / context roles (non-core)

• Platelet degranulation / mediator storage (PMID:15297306; Reactome R-HSA-114608).
• Prostaglandin-dependent ciliogenesis: ABCC4 exports the PGE2 signal that promotes ciliogenesis
  via intraflagellar transport PMID:25173977. ABCC4 acts upstream (transport), not as a cilium
  component.
• Efflux at the blood-brain barrier (PMID:26590417, PMID:30280653; NAS reviews).

Removed / corrected annotation

• GO:0016404 15-hydroxyprostaglandin dehydrogenase (NAD+) activity (NAS, PMID:7557451) — REMOVE.
  PMID:7557451 is about the HPGD / 15-PGDH enzyme, not ABCC4. ABCC4 is an ABC membrane transporter
  with no NAD(+)-dependent dehydrogenase domain; this enzymatic MF is biologically impossible for it and
  is a gene/term mis-attribution (recorded as a source_defects entry, WRONG_TERM/GOA_EBI, DELETE_ROW).
• GO:0098591 external side of apical plasma membrane (ISS, PMID:18619525) — MARK_AS_OVER_ANNOTATED.
  MRP4 is a polytopic integral membrane transporter, not a protein peripherally attached to the external
  face; apical plasma membrane (GO:0016324) captures the surface-biotinylation result correctly.
• Generic GO:0016020 membrane rows — TOO_GENERAL (plasma membrane / apical / basolateral asserted
  and accepted elsewhere).

Provenance notes

All quoted supporting_text was verified as a verbatim (whitespace-collapsed) substring of the cited
cached publication. Many primary transport papers are abstract-only in the cache
(full_text_available: false); experimental (EXP/IDA/IMP) annotations were accepted/deferred to the
curator per project policy rather than overruled on abstract-only evidence.

Generic CC/MF term convention (batch-2 review, 2026-11-11)

Applied consistently across ABCA8/ABCC1/ABCC3/ABCC4: GO:0016020 membrane -> MODIFY to GO:0005886 plasma membrane (paradigm MODIFY case); GO:0022857 transmembrane transporter activity -> TOO_GENERAL (entailed by the specific accepted transporter activities); GO:0005886 plasma membrane -> ACCEPT (the generic PM term is informative, and apical/basolateral sidedness is carried by the gene's own GO:0016324/GO:0016323 rows, not by blanket-MODIFYing the PM parent to a sub-domain).
This gene: changed its 3 GO:0016020 rows from TOO_GENERAL to MODIFY->GO:0005886, and GO:0022857 from ACCEPT to TOO_GENERAL; GO:0005886 rows already ACCEPT.