Haem carrier protein 1

Last updated
Putative type VI secretion protein
Identifiers
Organism Escherichia coli str. 042
SymbolEC042_4529
Alt. symbolsHCP1
Entrez 12885448
PDB 4HKH
RefSeq (Prot) WP_001007313.1
UniProt D3GUW0
Other data
Chromosome Genomic: 4.86 - 4.86 Mb
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Structures Swiss-model
Domains InterPro

Haem or Heme carrier protein 1 (HCP1) was originally identified as mediating heme-Fe transport although it later emerged that it was the SLC46A1 folate transporter. [1] [2]

Contents

HCP1 is a protein found in the small intestine that plays a role in the absorption of dietary heme, a form of iron that is only found in animal products. [3] [4] [5] Heme is an important nutrient for the body, as it is a component of many proteins, including hemoglobin, which carries oxygen in the blood. HCP1 is the only known heme transporter expressed in the small intestine and is therefore unique in its function and expression pattern. [4] HCP1 is a transmembrane protein that is expressed in the brush-border membrane of the small intestine, where it binds to heme and transports it into the enterocyte. [4]

The absorptive cell of the small intestine. HCP1 is particularly important in situations where dietary iron intake is low, as it allows for the efficient absorption of heme iron. HCP1 is also expressed in other tissues, including the liver and bone marrow, where it may play a role in the uptake of heme for the production of heme-containing proteins. Dysfunction of HCP1 has been associated with a range of conditions, including iron-deficiency anemia and certain types of cancer. [6] [4]

History

HCP1 is also known as proton-coupled folate transporter (PCFT), as it was initially identified as a transporter for folate, a type of vitamin B [7] However, subsequent studies revealed that HCP1 primarily functions as a heme transporter in the small intestine. [4]

Properties

HCP1 is a type of transmembrane protein that spans the membrane of the enterocyte in the small intestine. It has a large extracellular domain that binds to heme, as well as a smaller intracellular domain that interacts with protons to drive heme uptake. The body more easily absorbs heme iron than non-heme iron, which is found in plant-based foods. This is because heme iron is more bioavailable, meaning that the body can absorb and use it more efficiently. HCP1 plays a key role in the absorption of heme iron in the small intestine, particularly in situations where dietary iron intake is low. HCP1 expression is regulated by a number of factors, including iron status, dietary heme intake, and inflammation. Studies have shown that HCP1 expression is upregulated in response to low iron levels and decreased when iron levels are sufficient. [4]

Pathogenesis

Dysfunction of HCP1 has been associated with a range of conditions, including iron-deficiency anemia, thalassemia, and porphyria. HCP1 has also been implicated in the pathogenesis of certain types of cancer, including colorectal cancer and pancreatic cancer. [4] [8] [9] HCP1 is a promising target for the development of drugs that can modulate heme uptake and metabolism. Inhibitors of HCP1 have been developed as potential treatments for cancer, while activators of HCP1 may have therapeutic potential in the treatment of iron-deficiency anemia. [6]

structure

The structure of HCP1 is complex and involves interactions between multiple domains and regions of the protein. HCP1 is a transmembrane protein, a type of protein that spans the cell membrane with parts of it located both inside and outside of the cell. Spanning the membrane allows it to transport heme across the cell membrane. [6] HCP1 has a large extracellular domain that binds to heme with high affinity. This binding enables HCP1 to transport heme into the enterocyte in the small intestine. [4] [6] HCP1 is a proton-coupled transporter meaning that HCP1 relies on a proton gradient across the cell membrane to transport heme into the enterocyte. [4] The proton gradient uses the energy of protons to move heme across the cell membrane. [6] [4] While HCP1 is expressed in the small intestine, liver, and bone marrow, HCP1 is primarily expressed in the small intestine, where it plays a key role in heme absorption. In other tissues, such as the liver and bone marrow it may be involved in heme metabolism. HCP1 expression is regulated by iron status: HCP1 expression is upregulated in response to low iron levels and downregulated when iron levels are sufficient. [4] This regulation allows for efficient heme absorption in times of low iron intake. [4] Dysfunctional HCP1 has been associated with iron-deficiency anemia, thalassemia, and certain types of cancer. [4]

solubility

Haem Carrier Protein 1 (HCP1) is a membrane-bound protein that is embedded in the cell membrane. As such, it is not freely soluble in aqueous solutions like water. However, like other membrane proteins, using detergents, HCP1 can be solubilized and extracted from the cell membrane. Detergents are amphipathic molecules that have both hydrophobic and hydrophilic regions and can interact with both the membrane lipids and the protein molecules to solubilize them. The solubilization of HCP1 from the membrane requires careful selection of a suitable detergent and optimization of the conditions to preserve the protein's stability and activity. Common detergents used for the solubilization of membrane proteins include Triton X-100, dodecyl maltoside (DDM), and n-dodecyl-β-D-maltopyranoside (DDM). Once solubilized, HCP1 can be purified using various techniques, including chromatography and ultracentrifugation, to obtain a highly purified and homogeneous protein sample for further study. The solubility and stability of HCP1 can be affected by various factors, including pH, temperature, ionic strength, and the presence of other molecules or ligands that interact with the protein. [6] [4] some studies suggest that L-arginine can upregulate the expression of HCP-1, which may increase the uptake of cationic amino acids such as L-arginine in various cell types [10]

HCP1 is identical to the proton-coupled folate transporter (PCFT-SLC46A1). [2]

HCP1 is related to the Reduced Folate Carrier (RFC) SLC19A1. [2]

Related Research Articles

In cellular biology, active transport is the movement of molecules or ions across a cell membrane from a region of lower concentration to a region of higher concentration—against the concentration gradient. Active transport requires cellular energy to achieve this movement. There are two types of active transport: primary active transport that uses adenosine triphosphate (ATP), and secondary active transport that uses an electrochemical gradient. This process is in contrast to passive transport, which allows molecules or ions to move down their concentration gradient, from an area of high concentration to an area of low concentration, without energy.

<span class="mw-page-title-main">Intrinsic factor</span> Glycoprotein produced in the stomach which binds to vitamin B12

Intrinsic factor (IF), cobalamin binding intrinsic factor, also known as gastric intrinsic factor (GIF), is a glycoprotein produced by the parietal cells (in humans) or chief cells (in rodents) of the stomach. It is necessary for the absorption of vitamin B12 later on in the distal ileum of the small intestine. In humans, the gastric intrinsic factor protein is encoded by the CBLIF gene. Haptocorrin (transcobalamin I) is another glycoprotein secreted by the salivary glands which binds to vitamin B12. Vitamin B12 is acid-sensitive and in binding to haptocorrin it can safely pass through the acidic stomach to the duodenum.

<span class="mw-page-title-main">Enterocyte</span> Type of intestinal cell

Enterocytes, or intestinal absorptive cells, are simple columnar epithelial cells which line the inner surface of the small and large intestines. A glycocalyx surface coat contains digestive enzymes. Microvilli on the apical surface increase its surface area. This facilitates transport of numerous small molecules into the enterocyte from the intestinal lumen. These include broken down proteins, fats, and sugars, as well as water, electrolytes, vitamins, and bile salts. Enterocytes also have an endocrine role, secreting hormones such as leptin.

<span class="mw-page-title-main">Glucose transporter</span> Family of monosaccharide transport proteins

Glucose transporters are a wide group of membrane proteins that facilitate the transport of glucose across the plasma membrane, a process known as facilitated diffusion. Because glucose is a vital source of energy for all life, these transporters are present in all phyla. The GLUT or SLC2A family are a protein family that is found in most mammalian cells. 14 GLUTS are encoded by the human genome. GLUT is a type of uniporter transporter protein.

<span class="mw-page-title-main">Human iron metabolism</span> Iron metabolism in the body

Human iron metabolism is the set of chemical reactions that maintain human homeostasis of iron at the systemic and cellular level. Iron is both necessary to the body and potentially toxic. Controlling iron levels in the body is a critically important part of many aspects of human health and disease. Hematologists have been especially interested in systemic iron metabolism, because iron is essential for red blood cells, where most of the human body's iron is contained. Understanding iron metabolism is also important for understanding diseases of iron overload, such as hereditary hemochromatosis, and iron deficiency, such as iron-deficiency anemia.

<span class="mw-page-title-main">Folate deficiency</span> Abnormally low level of folate (vitamin B9) in the body

Folate deficiency, also known as vitamin B9 deficiency, is a low level of folate and derivatives in the body. This may result in a type of anemia in which red blood cells become abnormally large and is a late finding in folate deficiency and folate deficiency anemia is the term given for this medical condition. Signs of folate deficiency are often subtle. Symptoms may include feeling tired, heart palpitations, shortness of breath, feeling faint, open sores on the tongue, loss of appetite, changes in the color of the skin or hair, irritability, and behavioral changes. Temporary reversible infertility may occur. Folate deficiency anemia during pregnancy may give rise to the birth of low weight birth premature infants and infants with neural tube defects.

<span class="mw-page-title-main">Hephaestin</span> Mammalian protein found in Homo sapiens

Hephaestin, also known as HEPH, is a protein which in humans is encoded by the HEPH gene.

<span class="mw-page-title-main">Natural resistance-associated macrophage protein 2</span>

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<span class="mw-page-title-main">Thiamine transporter 1</span> Mammalian protein found in Homo sapiens

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<span class="mw-page-title-main">Iron in biology</span> Use of Iron by organisms

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<span class="mw-page-title-main">GLUT5</span> Protein-coding gene in the species Homo sapiens

GLUT5 is a fructose transporter expressed on the apical border of enterocytes in the small intestine. GLUT5 allows for fructose to be transported from the intestinal lumen into the enterocyte by facilitated diffusion due to fructose's high concentration in the intestinal lumen. GLUT5 is also expressed in skeletal muscle, testis, kidney, fat tissue (adipocytes), and brain.

<span class="mw-page-title-main">Folate transporter 1</span> Mammalian protein found in Homo sapiens

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<span class="mw-page-title-main">Peptide transporter 1</span> Mammalian protein found in Homo sapiens

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<span class="mw-page-title-main">Plasma membrane monoamine transporter</span> Protein-coding gene in the species Homo sapiens

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<span class="mw-page-title-main">Hereditary folate malabsorption</span> Medical condition

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<span class="mw-page-title-main">Proton-coupled folate transporter</span> Mammalian protein found in Homo sapiens

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<span class="mw-page-title-main">Natural resistance-associated macrophage protein</span> Family of transport proteins

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References

  1. ↑ Nakai Y, Inoue K, Abe N, Hatakeyama M, Ohta KY, Otagiri M, Hayashi Y, Yuasa H (August 2007). "Functional characterization of human proton-coupled folate transporter/heme carrier protein 1 heterologously expressed in mammalian cells as a folate transporter". The Journal of Pharmacology and Experimental Therapeutics. 322 (2): 469–76. doi:10.1124/jpet.107.122606. PMID   17475902. S2CID   23277839.
  2. 1 2 3 Zhao R, Aluri S, Goldman ID (February 2017). "The proton-coupled folate transporter (PCFT-SLC46A1) and the syndrome of systemic and cerebral folate deficiency of infancy: Hereditary folate malabsorption". Molecular Aspects of Medicine. 53: 57–72. doi:10.1016/j.mam.2016.09.002. PMC   5253092 . PMID   27664775.
  3. ↑ Tong Y, Guo M (January 2009). "Bacterial heme-transport proteins and their heme-coordination modes". Archives of Biochemistry and Biophysics. 481 (1): 1–15. doi:10.1016/j.abb.2008.10.013. PMC   2683585 . PMID   18977196.
  4. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 Shayeghi M, Latunde-Dada GO, Oakhill JS, Laftah AH, Takeuchi K, Halliday N, et al. (September 2005). "Identification of an intestinal heme transporter". Cell. 122 (5): 789–801. doi: 10.1016/j.cell.2005.06.025 . PMID   16143108. S2CID   9130882.
  5. ↑ Latunde-Dada GO, Takeuchi K, Simpson RJ, McKie AT (December 2006). "Haem carrier protein 1 (HCP1): Expression and functional studies in cultured cells". FEBS Letters. 580 (30): 6865–6870. doi: 10.1016/j.febslet.2006.11.048 . PMID   17156779. S2CID   34763873.
  6. 1 2 3 4 5 6 Krishnamurthy P, Xie T, Schuetz JD (June 2007). "The role of transporters in cellular heme and porphyrin homeostasis". Pharmacology & Therapeutics. 114 (3): 345–358. doi:10.1016/j.pharmthera.2007.02.001. PMID   17368550.
  7. ↑ Yasuda S, Hasui S, Kobayashi M, Itagaki S, Hirano T, Iseki K (February 2008). "The mechanism of carrier-mediated transport of folates in BeWo cells: the involvement of heme carrier protein 1 in placental folate transport". Bioscience, Biotechnology, and Biochemistry. 72 (2): 329–334. doi: 10.1271/bbb.70347 . PMID   18256483. S2CID   10650884.
  8. ↑ Ito H, Matsui H, Tamura M, Majima HJ, Indo HP, Hyodo I (July 2014). "Mitochondrial reactive oxygen species accelerate the expression of heme carrier protein 1 and enhance photodynamic cancer therapy effect". Journal of Clinical Biochemistry and Nutrition. 55 (1): 67–71. doi:10.3164/jcbn.14-27. PMC   4078070 . PMID   25120282.
  9. ↑ Hiyama K, Matsui H, Tamura M, Shimokawa O, Hiyama M, Kaneko T, et al. (2013-01-01). "Cancer cells uptake porphyrins via heme carrier protein 1". Journal of Porphyrins and Phthalocyanines. 17 (1n02): 36–43. doi:10.1142/S1088424612501192. ISSN   1088-4246.
  10. ↑ Kurokawa H, Ito H, Terasaki M, Matano D, Taninaka A, Shigekawa H, Matsui H (2019-09-12). "Nitric oxide regulates the expression of heme carrier protein-1 via hypoxia inducible factor-1α stabilization". PLOS ONE. 14 (9): e0222074. Bibcode:2019PLoSO..1422074K. doi: 10.1371/journal.pone.0222074 . PMC   6742216 . PMID   31513628.
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