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FLASH GENE
Symbol SLC4A4 contributors: mct - updated : 20-08-2015
HGNC name solute carrier family 4, sodium bicarbonate cotransporter, member 4
HGNC id 11030
PROTEIN
PHYSICAL PROPERTIES
STRUCTURE
motifs/domains
  • N-terminal cytosolic domain involved in protein interactions
  • 14 TMs in its transmembrane region
  • 5 transmembrane segments with greater average size compared with SLC4A1
  • hydrophilic intracellular N-terminal regions including binding sites for hemoglobin EPB41 and other proteins
  • a C cytoplasmic terminal forming the exchange channel, with a dihydrophobic FL motif (residues 1013-1014)
  • C-terminal transmembrane region is tightly folded with unique structural and functional features that differ from SLC4A1
    • secondary structure precise location of the FL motif in the primary sequence of SLC4A4 are strict requirements for the alpha-helical structure of the C-terminal cytoplasmic domain and for targeting of SLC4A4 to the basolateral membrane
    HOMOLOGY
    Homologene
    FAMILY
  • solute carrier family 4, sodium bicarbonate
  • anion exchanger family
  • xanthine/uracyl permease family
    • CATEGORY transport carrier
    SUBCELLULAR LOCALIZATION extracellular
        plasma membrane
    text basolateral membrane
    basic FUNCTION
  • involved in the transport of sodium and bicarbonate out of the corneal stroma and into the aqueous humor
  • mediating bicarbonate absorption from renal proximal tubules
  • electrogenic and plays an important role in bicarbonate reabsorption in kidney proximal tubule
  • SLC2A4, SLC4A4 play important roles in amelogenesis
  • playing a major role in renal bicarbonate absorption via proximal tubules and therefore is crucial for maintaining normal blood pH
  • transports sodium and bicarbonate across the basolateral membrane of the renal proximal tubule
  • its expression is required for the development of normal enamel
  • is electrogenic because it has an apparent Na+:HCO&
    • 8323;&
    8315; stoichiometry of 1:2 or 1:3
  • is a key element in a feedforward mechanism linking excitatory synaptic transmission to fast modulation of glycolysis in astrocytes
  • regulation of anion fluxes in insulin-producing cells may involve both SLC4A4 and ANO1
  • encodes electrogenic, amiloride-insensitive Na-HCO3 cotransport in proximal colon
  • is a high-affinity bicarbonate carrier in cortical astrocytes
  • SLC4A4 and the trafficking regulator gene COPA, plays an important role in early endosome maturation
  • COPA and SLC4A4 are required for cellular entry of arginine-rich peptides
  • major regulator of intracellular, and extracellular pH
    • CELLULAR PROCESS
    PHYSIOLOGICAL PROCESS
    PATHWAY
    metabolism
    signaling sensory transduction/vision
    a component
  • interaction with CA2/CA4 at the inner surface of the plasma membrane, indicating that SLC4A4/CAII interaction is needed for full pH(i) recovery activity
    • INTERACTION
    DNA
    RNA
    small molecule
    protein
  • target molecule of AHCYL1 (AHCYL1 may also be responsible for the characteristic difference in physiological roles of SLC4A4 variants)
  • target molecule of AHCYL1 and AHCYL1 has an important role in pH regulation through SLC4A4
  • AHCYL1 may be a cytosolic factor that modulates the apparent affinity for Mg2+ intracellular in inhibition of SLC4A in mammalian cells
  • site-specific interactions of HSPA13 with SLC4A4 and SLC9A1 and subsequent modulation of membrane transporter expression
  • AHCYL2 is a potential regulator of SLC4A4 in mammalian cells
    • cell & other
    REGULATION
    activated by directly stimulated by carbonic anhydrase (CA) II
    ASSOCIATED DISORDERS
    corresponding disease(s) RTA2
    Other morbid association(s)
    TypeGene ModificationChromosome rearrangementProtein expressionProtein Function
    tumoral     --low  
    associated with unfavorable prognosis in Colorectal cancer
    Susceptibility
    Variant & Polymorphism
    Candidate gene
    Marker
  • CEACAM7, SLC4A4, GCG and CLCA1 may be prognostic markers or therapeutic targets of Colorectal cancer
  • biomarker for thyroid cancer exhibiting differences in the correlation coefficients between benign and malignant samples that indicate its discriminatory power
    • Therapy target
    ANIMAL & CELL MODELS
  • (NBCe1&
    • 8722;/&
    8722; mice) have a severe phenotype, severe metabolic acidosis, growth retardation, reduced plasma Na+, hyperaldosteronism, splenomegaly, intestinal obstructions, and die before weaning , and also are described as having an abnormal dentition with “chalk-white” and “brittle” enamel
  • mice lacking NBCe1 have enamel abnormalities