Role for copper in the cellular and regulatory effects of heme-hemopexin

Smith, Ann; Rish, Kimberly; Lovelace, Rachel; Hackney, Jennifer F.; Helston, Rachel M.

doi:10.1007/s10534-008-9178-z

Cited by 14 publications

(15 citation statements)

References 73 publications

(93 reference statements)

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“…1 and 2). This three-dimensional structure reveals that the Arg-GlyGlu sequence (residues 190-192) proposed above to act as a site for interaction with cell surfaces is highly exposed on the surface of the protein and near the JEN14 epitope [residues 123-143, which include the Arg-Gly-Glu sequence (128)(129)(130)] that was predicted to be one site recognized by the rabbit hemopexinheme receptor.…”

Section: Discussionmentioning

confidence: 95%

“…Acidic patches at the narrow opening of the central tunnels in the b-propellers have been proposed as potential binding sites for metal ions, particularly Ca 2þ . 1,8 An homology model for the structure of the human hemopexin-heme complex based on the structure of the rabbit protein was used to identify several additional, putative binding sites for metal ions on human hemopexin 21 and has led to speculation that hemopexin and the hemopexin-heme complex might 130 On the other hand, at neutral pH Ca 2þ promotes the binding of heme 68 and increases the thermal stability (T m ) of the hemopexin-heme complex. 21 All of these observations, as well as specific ion effects on the dissociation of heme from the hemopexin-heme complex, 57,68,131 suggest a means by which the interaction of the protein with metal ions may promote transfer and binding of heme to hemopexin in blood plasma, release of heme from the hemopexin-heme complex in the endosome, and, as a result, promotion of the known anti-oxidant capacity of hemopexin.…”

Section: Hemopexin As a Metal Ion Binding Proteinmentioning

confidence: 99%

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An alternative view of the proposed alternative activities of hemopexin

2011

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Hemopexin is a plasma protein that plays a well-established biological role in sequestering heme that is released into the plasma from hemoglobin and myoglobin as the result of intravascular or extravascular hemolysis as well as from skeletal muscle trauma or neuromuscular disease. In recent years, a variety of additional biological activities have been attributed to hemopexin, for example, hyaluronidase activity, serine protease activity, proinflammatory and anti-inflammatory activity as well as suppression of lymphocyte necrosis, inhibition of cellular adhesion, and binding of divalent metal ions. This review examines the challenges involved in the purification of hemopexin from plasma and in the recombinant expression of hemopexin and evaluates the questions that these challenges and the characteristics of hemopexin raise concerning the validity of many of the new activities proposed for this protein. As well, an homology model of the three-dimensional structure of human hemopexin is used to reveal that the protein lacks the catalytic triad that is characteristic of many serine proteases but that hemopexin possesses two highly exposed Arg-Gly-Glu sequences that may promote interaction with cell surfaces.

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Section: Discussionmentioning

confidence: 95%

Section: Hemopexin As a Metal Ion Binding Proteinmentioning

confidence: 99%

An alternative view of the proposed alternative activities of hemopexin

2011

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“…With time, endosomal pH decreases by ATP-dependent processes (51,55,56) to a value (pH ϳ5) at which the thermal stability of the Hx-heme complex is greatly diminished (25). Although the metal ion content of endosomes is currently unknown, a recent report suggests that endocytosis of the Hxheme complex increases cytosolic copper levels in Hepa hepatoma cells (12). Certainly the availability of Zn 2ϩ or Cu 2ϩ in early endosomes could accelerate the release of heme from the Hx-heme complex prior to a significant decrease in pH.…”

Section: Discussionmentioning

confidence: 99%

“…Hx may also have a role in protection of neural tissue, and it exhibits other activities that include inhibition of necrosis and adhesion of polymorphonuclear leukocytes (8 -10). The dominant form of circulating Hx is the apoprotein 3 (6 -25 M (1)), which upon binding heme forms the Hx-heme complex that is recognized by hepatic receptors and removed from circulation by endocytosis (3,11,12). Subsequent to endocytosis, heme is dissociated from the Hx-heme complex and oxidized by heme oxygenase-1 to release iron that is then added to ferritin stores (13,14).…”

mentioning

confidence: 99%

Metal Ions and Electrolytes Regulate the Dissociation of Heme from Human Hemopexin at Physiological pH

Mauk

2010

Journal of Biological Chemistry

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The stability of the hemopexin-heme (Hx-heme) complex to dissociation of the heme prosthetic group has been examined in bicarbonate buffers in the presence and absence of various divalent metal ions. In NH 4 HCO 3 buffer (pH 7.4, 20 mM, 25°C) containing Zn 2؉ (100 M), 14% of the heme dissociates from this complex (4.5 M) within 10 min, and 50% dissociates within 2 h. In the absence of metal ions, the rate of dissociation of this complex is far lower, is decreased further in KHCO 3 solution, and is minimal in NaHCO 3 . In NH 4 HCO 3 buffer, dissociation of the Hx-heme complex is accelerated by addition of divalent metals with decreasing efficiency in the order ZnAddition of Ca 2؉ prior to addition of Zn 2؉ stabilizes the Hx-heme complex to dissociation of the heme group, and addition of Ca 2؉ after Zn 2؉ -induced dissociation of the Hxheme complex results in re-formation of the Hx-heme complex. These effects are greatly accelerated at 37°C and diminished in other buffers. Overall, the solution conditions that promote formation of the Hx-heme complex are similar to those found in blood plasma, and conditions that promote release of heme are similar to those that the Hx-heme complex should encounter in endosomes following endocytosis of the complex formed with its hepatic receptor.The plasma protein hemopexin (Hx, 2 MW ϳ58,000) is a positive acute phase reactant glycoprotein with the primary role of scavenging heme released from methemoglobin and other heme proteins as the result of hemolysis, rhabdomyolysis, or ischemia-reperfusion injury (1-3). In doing so, Hx prevents the oxidative damage and pro-inflammatory effects of free heme (4 -6) as demonstrated by the increased sensitivity of Hx-null mice (4, 7) to heme overload and development of heme-catalyzed oxidative damage to the vasculature, liver, and kidneys. Hx may also have a role in protection of neural tissue, and it exhibits other activities that include inhibition of necrosis and adhesion of polymorphonuclear leukocytes (8 -10). The dominant form of circulating Hx is the apoprotein 3 (6 -25 M (1)), which upon binding heme forms the Hx-heme complex that is recognized by hepatic receptors and removed from circulation by endocytosis (3,11,12). Subsequent to endocytosis, heme is dissociated from the Hx-heme complex and oxidized by heme oxygenase-1 to release iron that is then added to ferritin stores (13,14). The protein component of the endocytosed Hx-heme complex that is liberated in this manner either returns to circulation (15-18) or undergoes lysosomal degradation (11,18).Heme binds to Hx with extremely high affinity (19, 20) even though the crystal structure for the rabbit Hx-heme complex indicates that the heme is more exposed to solvent than is the case for many heme proteins (21, 22). The Hx-heme complex is an unusual b-type hemeprotein in that the axial ligands that coordinate the heme iron are not located in a structurally constrained region of the protein, and one of the axial histidine ligands is located in the flexible linker region that connects...

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“…Activation of MT-1 gene transcription as a consequence of Hx-mediated heme transport may occur during endocytosis or via an indirect mechanism triggered by the interaction of heme-Hx with the Hx receptor on the cell surface. Recently Smith et al demonstrated that the correct hypothesis was the first one: mainly copper, than the heme-Hx complex has been found to have an essential role in MT-1 induction (Smith et al, 2008). Copper endocytosis together with that of heme-Hx provides a mean to facilitate heme release from Hx in the maturing endosomes, by preventing the rebinding of heme to Hx.…”

Section: Hemopexin-mediated Regulation Of Genes Involved In Iron Recymentioning

confidence: 99%