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How mammals acquire and distribute iron needed for oxygen-based metabolism.

Rouault TA - PLoS Biol. (2003)

View Article: PubMed Central - PubMed

Affiliation: Cell Biology and Metabolism Branch of the National Institute of Child Health and Human Development in Bethesda, Maryland, USA. trou@helix.nih.gov

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Virtually all cells and organisms require iron to perform basic cellular processes... In respiration, iron proteins capture energy released from oxidation of food by synthesizing high-energy compounds, such as NADH, that are used to fuel cellular metabolism... Most of the iron that gains access to the circulating blood binds tightly to serum transferrin, an abundant protein that binds one (monoferric) or two ferric iron atoms (diferric or holotransferrin) with high affinity... When ferric iron is bound to transferrin, it is nonreactive, meaning that it does not engage in single-electron transfers and it does not threaten other proteins and blood vessel walls with its reactivity... Cells accomplish this task by synthesizing transferrin receptors, proteins that are present as pairs (dimers) on the cell surface... When holotransferrin binds to the transferrin receptor, the complex of transferrin bound to the receptor is internalized by a process known as clathrin-mediated endocytosis, a mechanism for moving the surface receptor complexes into discrete membrane-bound physical environments within cells known as endosomal vesicles... When proteins bind to one another in cells, it is usually because they are collaborating to accomplish an important task... In an article in this issue of PLoS Biology by, the authors have substituted specific amino acids in the transferrin receptor with different amino acids to determine whether they are important in binding either HFE or diferric transferrin... They have reached an interesting conclusion: their data indicate that diferric transferrin and HFE bind to physically and functionally overlapping sites on the transferrin receptor... A logical extension of this conclusion is that if each monomer in the transferrin receptor dimer were bound to HFE, the transferrin receptor would not be able to bind and internalize diferric transferrin... Thus, transferrin and the transferrin receptor are proteins that play central roles in mammalian iron metabolism... Transferrin solves the problem of how to move iron through the body safely and efficiently... The transferrin receptor is present on the surface of only those cells that need iron, because cells regulate how much transferrin receptor they make according to their needs... Clearly, HFE binding will be important in transferrin receptor function, but we do not yet understand how it functions.

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Binding of TransferrinTransferrin (purple rhombus) binds two ferric iron atoms (orange squares) and circulates in the bloodstream until it comes into contact with transferrin receptors, which pair together to form dimers (red torpedo shapes) on the plasma membrane surface of cells. A complex of HFE (blue square) and β2-microglobulin (green square) binds to the transferrin receptor. Notably, the binding site for HFE overlaps the potential binding site of transferrin. Since it is likely that HFE associates with transferrin receptors shortly after synthesis, before the complex arrives at the plasma membrane, HFE can thus potentially prevent iron uptake through the transferrin receptor. Once transferrin binds the transferrin receptor (assuming that both potential binding sites are not blocked by HFE), the complex internalizes in an endosome, where acidification promotes release of ferric iron, and reduction by addition of an electron (e–) to ferrous or diferric iron allows transport of free iron from the endosome, using the divalent metal transporter, DMT1, to the cytosol. Upon release into the cytosol, iron can be incorporated into proteins, and its presence can be sensed by iron regulatory proteins (IRPs).
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pbio.0000079-g001: Binding of TransferrinTransferrin (purple rhombus) binds two ferric iron atoms (orange squares) and circulates in the bloodstream until it comes into contact with transferrin receptors, which pair together to form dimers (red torpedo shapes) on the plasma membrane surface of cells. A complex of HFE (blue square) and β2-microglobulin (green square) binds to the transferrin receptor. Notably, the binding site for HFE overlaps the potential binding site of transferrin. Since it is likely that HFE associates with transferrin receptors shortly after synthesis, before the complex arrives at the plasma membrane, HFE can thus potentially prevent iron uptake through the transferrin receptor. Once transferrin binds the transferrin receptor (assuming that both potential binding sites are not blocked by HFE), the complex internalizes in an endosome, where acidification promotes release of ferric iron, and reduction by addition of an electron (e–) to ferrous or diferric iron allows transport of free iron from the endosome, using the divalent metal transporter, DMT1, to the cytosol. Upon release into the cytosol, iron can be incorporated into proteins, and its presence can be sensed by iron regulatory proteins (IRPs).

Mentions: I thank Caroline Philpott for allowing me to incorporate her original artwork into the figure.


How mammals acquire and distribute iron needed for oxygen-based metabolism.

Rouault TA - PLoS Biol. (2003)

Binding of TransferrinTransferrin (purple rhombus) binds two ferric iron atoms (orange squares) and circulates in the bloodstream until it comes into contact with transferrin receptors, which pair together to form dimers (red torpedo shapes) on the plasma membrane surface of cells. A complex of HFE (blue square) and β2-microglobulin (green square) binds to the transferrin receptor. Notably, the binding site for HFE overlaps the potential binding site of transferrin. Since it is likely that HFE associates with transferrin receptors shortly after synthesis, before the complex arrives at the plasma membrane, HFE can thus potentially prevent iron uptake through the transferrin receptor. Once transferrin binds the transferrin receptor (assuming that both potential binding sites are not blocked by HFE), the complex internalizes in an endosome, where acidification promotes release of ferric iron, and reduction by addition of an electron (e–) to ferrous or diferric iron allows transport of free iron from the endosome, using the divalent metal transporter, DMT1, to the cytosol. Upon release into the cytosol, iron can be incorporated into proteins, and its presence can be sensed by iron regulatory proteins (IRPs).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC300689&req=5

pbio.0000079-g001: Binding of TransferrinTransferrin (purple rhombus) binds two ferric iron atoms (orange squares) and circulates in the bloodstream until it comes into contact with transferrin receptors, which pair together to form dimers (red torpedo shapes) on the plasma membrane surface of cells. A complex of HFE (blue square) and β2-microglobulin (green square) binds to the transferrin receptor. Notably, the binding site for HFE overlaps the potential binding site of transferrin. Since it is likely that HFE associates with transferrin receptors shortly after synthesis, before the complex arrives at the plasma membrane, HFE can thus potentially prevent iron uptake through the transferrin receptor. Once transferrin binds the transferrin receptor (assuming that both potential binding sites are not blocked by HFE), the complex internalizes in an endosome, where acidification promotes release of ferric iron, and reduction by addition of an electron (e–) to ferrous or diferric iron allows transport of free iron from the endosome, using the divalent metal transporter, DMT1, to the cytosol. Upon release into the cytosol, iron can be incorporated into proteins, and its presence can be sensed by iron regulatory proteins (IRPs).
Mentions: I thank Caroline Philpott for allowing me to incorporate her original artwork into the figure.

View Article: PubMed Central - PubMed

Affiliation: Cell Biology and Metabolism Branch of the National Institute of Child Health and Human Development in Bethesda, Maryland, USA. trou@helix.nih.gov

AUTOMATICALLY GENERATED EXCERPT
Please rate it.

Virtually all cells and organisms require iron to perform basic cellular processes... In respiration, iron proteins capture energy released from oxidation of food by synthesizing high-energy compounds, such as NADH, that are used to fuel cellular metabolism... Most of the iron that gains access to the circulating blood binds tightly to serum transferrin, an abundant protein that binds one (monoferric) or two ferric iron atoms (diferric or holotransferrin) with high affinity... When ferric iron is bound to transferrin, it is nonreactive, meaning that it does not engage in single-electron transfers and it does not threaten other proteins and blood vessel walls with its reactivity... Cells accomplish this task by synthesizing transferrin receptors, proteins that are present as pairs (dimers) on the cell surface... When holotransferrin binds to the transferrin receptor, the complex of transferrin bound to the receptor is internalized by a process known as clathrin-mediated endocytosis, a mechanism for moving the surface receptor complexes into discrete membrane-bound physical environments within cells known as endosomal vesicles... When proteins bind to one another in cells, it is usually because they are collaborating to accomplish an important task... In an article in this issue of PLoS Biology by, the authors have substituted specific amino acids in the transferrin receptor with different amino acids to determine whether they are important in binding either HFE or diferric transferrin... They have reached an interesting conclusion: their data indicate that diferric transferrin and HFE bind to physically and functionally overlapping sites on the transferrin receptor... A logical extension of this conclusion is that if each monomer in the transferrin receptor dimer were bound to HFE, the transferrin receptor would not be able to bind and internalize diferric transferrin... Thus, transferrin and the transferrin receptor are proteins that play central roles in mammalian iron metabolism... Transferrin solves the problem of how to move iron through the body safely and efficiently... The transferrin receptor is present on the surface of only those cells that need iron, because cells regulate how much transferrin receptor they make according to their needs... Clearly, HFE binding will be important in transferrin receptor function, but we do not yet understand how it functions.

Show MeSH
Related in: MedlinePlus