Ololade fatunmbi

From Proteopedia

Revision as of 20:52, 16 December 2014

Haptoglobin-Hemoglobin Structure

Hemoglobin (Hb) is arguably one of the most studied proteins of all time. Hb is essential for life because it transports oxygen from organs to tissues so that we can have energy. Like most entities in life, too much of something may actually harm mast cause damage. High concentrations of Hb released from red blood cells could cost oxidative damage to the body. Haptoglobin, an acute phase protein, counteracts the negative physiological consequences of intravascular hemolysis by binding to the free dimers of Hb with the highest affinity known in nature (Kd ~1 × 10–15 mol/L) (2-4)

Hp is found in nearly all mammals and some vertebrates. In humans, there are two allelic forms, Hp1 and Hp2, which manifest three phenotypes (2). Hp1 is responsible for the Hp1-1 phenotype. Partial intragenic duplication in Hp1 gives rise to Hp2 allele, which is responsible for two phenotypes, Hp2-1 and Hp 2-2 (2). Both in vitro and in vivo studies have established that subjects with the Hp1-1 phenotype are more likely to resist cellular oxidative stress than those with the Hp2-2 phenotype, with Hp2-1 being intermediate (6).

Function

Hb is physiologically a found in red blood cells. During intravascular hemolysis, red bloods cells are ruptured and Hb is released from red blood cells in to the extracellular environment. When Hb is in the extracellular environment, it dissociates into dimers exposing and could react with .

and exposes an recognized by the multifunctional receptor, CD163. The Hp/Hb complex binds CD-163 with high affinity and mediates haptoglobin-hemoglobin endocytosis and degradation (2).

Structural highlights

Haptoglobin
Hp alone's crystal structure has not yet been elucidated. Hp1-1 is ~90kda and consists of of the two α (light chains) and two β (heavy chains) linked by disulfide bond (Cys33). There are altogether 4 disulfides bonds (cys72 and cys 105) hold the light and heavy chain together). There are also found on a each monomer of Hp1-1 (16).

Hemoglobin-Haptoglobin Complex
What makes the binding between Hp so tight and nearly irreversible (Kd ~1 × 10–15 mol/L)? Recently the crystal structure of porcine haptoglobin in complex with hemoglobin was solved (Figure 4a) and reported (17). Porcine Hp shares 92% homology with human Hp 1-1 (17). The interaction between Hb and Hp is composed of various hydrophobic and and other electrostatic interactions.

Disease

Prevention of Renal Damage: Intravascular hemolysis accounts for approximately 15% of total red blood cell destruction and occurs in several diseases including sickle-cell anemia and malaria (1). Another consequence caused by free hemoglobin is oxidative damage in renal tissues following intravascular hemolysis (7). Yet when haptoglobin binds to hemoglobin, the complex is too large to pass through the glomeruli of the kidney and will be removed via the reticuloendothelial system (7). Therefore Hb induced injury to the parenchyma is prevented by haptoglobin (12).

Antibacterial Activity: When hemoglobin becomes non-covalently bound to haptoglobin, Hb and iron are no longer available to Escherichia coli and other bacteria that require iron (7). Eaton was able to demonstrate that when Hp was given to rats that have been intraperitoneally injected with E. Coli and hemoglobin, Hp was able to prevent fatal effects (8).

Antioxidant Activity: Haptoglobin has a significant role as an antioxidant (9). Free hemoglobin also increases the peroxidation of purified arachidonic acid and other polyunsaturated fatty acids within neuronal cell membranes (10). Iron released from heme proteins can catalyze oxidative injury to neuronal cell membranes and might have a role in posttraumatic central nervous system (CNS) damage (10). Haptoglobin, binds to Hb and removes it from the circulation and prevents iron-stimulated formation of oxygen radicals (11).

Relevance

In the field of drug delivery, plasma proteins have been sought out as targets for drug delivery of blood-related diseases.

My Research Interest

I am focused on the structural elucidation of Hp and it's interact physiological partners through molecular modeling and native mass spectrometry.

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References

Ololade Fatunmbi. Click above on edit this page to modify. Be careful with the < and > signs. You may include any references to papers as in: the use of JSmol in Proteopedia ^[1] or to the article describing Jmol ^[2] to the rescue.