Retinol binding protein 4

Retinol binding protein 4, also known as RBP4, is a transporter protein for retinol (vitamin A alcohol). RBP4 has a molecular weight of approximately 21 kDa and is encoded by the RBP4 gene in humans. It is mainly, though not exclusively, synthesized in the liver and circulates in the bloodstream as a hepatokine bound to retinol in a complex with transthyretin. RBP4 has been a drug target for ophthalmology research due to its role in vision. RBP4 may also be involved in metabolic diseases as suggested by recent studies.

RBP4
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 1BRP, 1BRQ, 1JYD, 1JYJ, 1QAB, 1RBP, 1RLB, 2WQ9, 2WQA, 2WR6, 3BSZ, 3FMZ, 4O9S, 4PSQ
Identifiers
Aliases	RBP4, MCOPCB10, RDCCAS, retinol binding protein 4
External IDs	OMIM: 180250 MGI: 97879 HomoloGene: 4908 GeneCards: RBP4
Gene location (Human) Chr. Chromosome 10 (human) Band 10q23.33 Start 93,591,687 bp End 93,601,744 bp
Gene location (Mouse) Chr. Chromosome 19 (mouse) Band 19 C2|19 32.75 cM Start 38,105,077 bp End 38,113,729 bp
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in right lobe of liver subcutaneous adipose tissue pituitary gland anterior pituitary abdominal fat tibia synovial joint nucleus accumbens kidney pericardium Top expressed in left lobe of liver yolk sac gallbladder white adipose tissue brown adipose tissue ascending aorta primitive streak subcutaneous adipose tissue islet of Langerhans aortic valve More reference expression data BioGPS More reference expression data
Gene ontology Molecular function retinol transmembrane transporter activity transporter activity protein binding retinoid binding protein heterodimerization activity retinol binding retinal binding small molecule binding Cellular component cytosol extracellular region extracellular exosome extracellular space protein-containing complex Biological process eye development gluconeogenesis heart trabecula formation response to retinoic acid glucose homeostasis response to stimulus cardiac muscle tissue development lung development vagina development urinary bladder development retinol metabolic process embryonic organ morphogenesis embryonic skeletal system development retinoid metabolic process female genitalia morphogenesis uterus development heart development maintenance of gastrointestinal epithelium retinol transport embryonic retina morphogenesis in camera-type eye response to ethanol negative regulation of cardiac muscle cell proliferation visual perception positive regulation of insulin secretion transport Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 5950 19662 Ensembl ENSG00000138207 ENSMUSG00000024990 UniProt P02753 Q00724 RefSeq (mRNA) NM_006744 NM_001323517 NM_001323518 NM_001159487 NM_011255 RefSeq (protein) NP_001310446 NP_001310447 NP_006735 NP_001152959 NP_035385 Location (UCSC) Chr 10: 93.59 – 93.6 Mb Chr 19: 38.11 – 38.11 Mb PubMed search
Wikidata
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Function

This protein belongs to the lipocalin family and is the specific carrier for retinol (vitamin A) in the blood. It delivers retinol from the liver stores to the peripheral tissues. In plasma, the RBP-retinol complex interacts with transthyretin, which prevents its loss by filtration through the kidney glomeruli. A deficiency of vitamin A blocks secretion of the binding protein posttranslationally and results in defective delivery and supply to the epidermal cells.

Structure

Two molecules of RBP4 (in yellow and red) bound to retinol (in orange) complexed with four molecules of TTR (in purple and blue)

RBP4 is a single polypeptide chain with a hydrophobic pocket where retinol binds. The RBP4-retinol complex then binds transthyretin in circulation to prevent renal filtration of RBP4.

In serum, TTR and RBP4 bind in a 1 to 1 stoichiometry (two molecules of TTR combine with two molecules of RBP4 to form a complex with a total molecular weight of approximately 80,000 daltons).

Clinical significance

Retinol-binding protein 4 has been a drug target for eye diseases as RBP4 is the sole carrier for retinol, which is an essential nutrient for the visual cycle. Animal studies using RBP4-antagonists showed that lowering RBP4 can lead to reduction in the accumulation of lipofuscin that leads to vision loss in eye diseases like Stargardt's disease and macular degeneration. An animal study using ABCA4 knockout mouse proved that reduction in serum RBP4 level could inhibit lipofuscin without inhibiting the visual cycle.[ref] One clinical study in age-related macular degeneration (AMD) was conducted using Fenretinide. The study showed trends in reducing lesion growth rate in AMD and rate of conversion from early stage AMD (dry AMD) to late stage AMD (wet AMD) without serious side effects.

RBP4 has recently been described as an adipokine that contributes to insulin resistance and diabetes in the AG4KO mouse model. In addition to the liver, RBP4 is also secreted by adipocytes of the fat tissue in a smaller portion and acts as a signal to surrounding cells, when there is a decrease in plasma glucose concentration. It is suspected that an elevated level of RBP4 attracts macrophages to the fat tissue, causes local inflammation, and leads to insulin resistance.

Mutations in the RBP4 gene have recently been linked to a form of autosomal dominant microphthalmia, anophthalmia, and coloboma (MAC) disease. A unique feature of this disease is the maternal inheritance effect, when a fetus inherits a mutated copy of the RBP4 gene from its mother, but not from its father. The physiologic basis lies in pregnancy whereby the mutated gene product, retinol binding protein (RBP), has negative effects in transferring vitamin A from maternal liver storage sites to the placenta, and then again on the fetal circulation side when delivering vitamin A from the placenta to developing fetal tissues, most notably the developing eye. This 'double whammy' effect does not exist when the mutant RBP4 gene is inherited from the father. The above mechanism is separate from previously known types of maternal inheritance effects such as genomic imprinting, mitochondrial inheritance, or maternal oocyte mRNA transfer. The authors of the above study cite the potential of vitamin A supplementation in pregnant females who are known to carry an RBP4 mutation with retinyl ester which utilizes an RBP-independent pathway to deliver retinoids from the maternal intestines directly to the placenta and ultimately is uptaken by the fetus. The key would be to supplement during the first several months of life when the eye begins to develop, as supplementing later in pregnancy would be too late to avoid any potential MAC disease.

See also

• Retinol
• Adipokine
• Transthyretin (TTR)

Further reading

• Quadro L, Hamberger L, Colantuoni V, Gottesman ME, Blaner WS (December 2003). "Understanding the physiological role of retinol-binding protein in vitamin A metabolism using transgenic and knockout mouse models". Molecular Aspects of Medicine. 24 (6): 421–30. doi:10.1016/S0098-2997(03)00038-4. PMID 14585313.
• Newcomer ME, Ong DE (October 2000). "Plasma retinol binding protein: structure and function of the prototypic lipocalin". Biochimica et Biophysica Acta (BBA) - Protein Structure and Molecular Enzymology. 1482 (1–2): 57–64. doi:10.1016/s0167-4838(00)00150-3. PMID 11058747.
• Fex G, Hansson B (February 1979). "Retinol-binding protein from human urine and its interaction with retinol and prealbumin". European Journal of Biochemistry. 94 (1): 307–13. doi:10.1111/j.1432-1033.1979.tb12896.x. PMID 571335.
• Rask L, Anundi H, Peterson PA (August 1979). "The primary structure of the human retinol-binding protein". FEBS Letters. 104 (1): 55–8. doi:10.1016/0014-5793(79)81084-4. PMID 573217. S2CID 8540537.
• Fex G, Albertsson PA, Hansson B (September 1979). "Interaction between prealbumin and retinol-binding protein studied by affinity chromatography, gel filtration and two-phase partition". European Journal of Biochemistry. 99 (2): 353–60. doi:10.1111/j.1432-1033.1979.tb13263.x. PMID 574085.
• Monaco HL, Zanotti G (April 1992). "Three-dimensional structure and active site of three hydrophobic molecule-binding proteins with significant amino acid sequence similarity". Biopolymers. 32 (4): 457–65. doi:10.1002/bip.360320425. PMID 1623143. S2CID 34994569.
• Cowan SW, Newcomer ME, Jones TA (1990). "Crystallographic refinement of human serum retinol binding protein at 2A resolution". Proteins. 8 (1): 44–61. doi:10.1002/prot.340080108. PMID 2217163. S2CID 21613341.
• D'Onofrio C, Colantuoni V, Cortese R (August 1985). "Structure and cell-specific expression of a cloned human retinol binding protein gene: the 5'-flanking region contains hepatoma specific transcriptional signals". The EMBO Journal. 4 (8): 1981–9. doi:10.1002/j.1460-2075.1985.tb03881.x. PMC 554451. PMID 2998779.
• Pfeffer BA, Clark VM, Flannery JG, Bok D (July 1986). "Membrane receptors for retinol-binding protein in cultured human retinal pigment epithelium". Investigative Ophthalmology & Visual Science. 27 (7): 1031–40. PMID 3013795.
• Kameko M, Ichikawa M, Katsuyama T, Kanai M, Kato M, Akamatsu T (April 1986). "Immunohistochemical localization of plasma retinol-binding protein and prealbumin in human pancreatic islets". The Histochemical Journal. 18 (4): 164–8. doi:10.1007/BF01676116. PMID 3525470. S2CID 2959823.
• Siegenthaler G, Saurat JH (April 1987). "Loss of retinol-binding properties for plasma retinol-binding protein in normal human epidermis". The Journal of Investigative Dermatology. 88 (4): 403–8. doi:10.1111/1523-1747.ep12469731. PMID 3559267.
• Rask L, Vahlquist A, Peterson PA (November 1971). "Studies on two physiological forms of the human retinol-binding protein differing in vitamin A and arginine content". The Journal of Biological Chemistry. 246 (21): 6638–46. doi:10.1016/S0021-9258(19)34162-6. PMID 5132677.
• Colantuoni V, Romano V, Bensi G, Santoro C, Costanzo F, Raugei G, Cortese R (November 1983). "Cloning and sequencing of a full length cDNA coding for human retinol-binding protein". Nucleic Acids Research. 11 (22): 7769–76. doi:10.1093/nar/11.22.7769. PMC 326530. PMID 6316270.
• Newcomer ME, Jones TA, Aqvist J, Sundelin J, Eriksson U, Rask L, Peterson PA (July 1984). "The three-dimensional structure of retinol-binding protein". The EMBO Journal. 3 (7): 1451–4. doi:10.1002/j.1460-2075.1984.tb01995.x. PMC 557543. PMID 6540172.
• Rask L, Anundi H, Böhme J, Eriksson U, Ronne H, Sege K, Peterson PA (February 1981). "Structural and functional studies of vitamin A-binding proteins". Annals of the New York Academy of Sciences. 359 (1): 79–90. Bibcode:1981NYASA.359...79R. doi:10.1111/j.1749-6632.1981.tb12739.x. PMID 6942701. S2CID 5781208.
• Jaconi S, Rose K, Hughes GJ, Saurat JH, Siegenthaler G (June 1995). "Characterization of two post-translationally processed forms of human serum retinol-binding protein: altered ratios in chronic renal failure". Journal of Lipid Research. 36 (6): 1247–53. doi:10.1016/S0022-2275(20)41132-0. PMID 7666002.
• Berni R, Malpeli G, Folli C, Murrell JR, Liepnieks JJ, Benson MD (September 1994). "The Ile-84-->Ser amino acid substitution in transthyretin interferes with the interaction with plasma retinol-binding protein". The Journal of Biological Chemistry. 269 (38): 23395–8. doi:10.1016/S0021-9258(17)31527-2. PMID 8089102.
• Seeliger MW, Biesalski HK, Wissinger B, Gollnick H, Gielen S, Frank J, Beck S, Zrenner E (January 1999). "Phenotype in retinol deficiency due to a hereditary defect in retinol binding protein synthesis". Investigative Ophthalmology & Visual Science. 40 (1): 3–11. PMID 9888420.

External links

• RBP4+protein,+human at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
• Overview of all the structural information available in the PDB for UniProt: P02753 (Retinol-binding protein 4) at the PDBe-KB.