Ololade fatunmbi
From Proteopedia
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Structure of the Porcine Hemoglobin-Haptoglobin Complex: Color Code
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Summary
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. However, like most entities in life, too much of something may actually be harmful. through a process called intravascular hemolysis, high concentrations of Hb are released from red blood cells into the extracellular environment which could cause oxidative damage to our tissues. Haptoglobin (Hp), an acute phase glycoprotein, counteracts the negative physiological consequences of intravascular hemolysis by binding Hb in one of strongest non-covalent events known in nature (Kd ~1 × 10–15 mol/L) (2-4). See Figure 1.
Function
Hb is physiologically a found in red blood cells. During intravascular hemolysis, a process that accounts for approximately 15% of total red blood cell destruction, red blood cells are ruptured and Hb is released into the extracellular environment. Hb dissociates into dimers in the extracellular exposing . Hb could cost oxidative damage to the body by reacting with small molecules in circulation such as peroxide.
Its prosthetic group, heme, is lipophilic and readily intercalates into cell membranes to disrupt the lipid bilayers (3). Iron present in heme catalyzes the generation of reactive oxygen species (ROS) through the Fenton and Haber-Weiss reactions (Figures 2). Hb could cost oxidative damage to the body by reacting with small molecules in circulation such as peroxide.
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).
Structural Highlights
Haptoglobin
Hp alone's crystal structure has not yet been elucidated. Hp1-1 is ~90kda and consists of of the two light chains and two heavy chains linked by the disulfide bond formed by . Altogether there are4 disulfides bonds on Hp and hold the light and heavy chain together. There are also found on a each monomer of Hp1-1 (16).
The light chain of Hp shares high homology with complement control proteins while the heavy chain is very homologous with serine proteases. Although Hp is not an active protease, the Hb-binding site in Hp is located in the region responsible for substrate specificity in other serene proteases (17). In serine proteases, the typical active-site residues are, -histidine-57 and serine-195. In haptoglobin these residues are replaced by lysine and alanine, respectively (18). However, a substrate specific residue in trypsin (aspartic acid-189) does occur in haptoglobin (18).
Hemoglobin-Haptoglobin Complex
What makes the binding between Hp so tight and nearly irreversible? Recently, the crystal structure of porcine haptoglobin in complex with hemoglobin was solved and revealed residues involved in Hb-Hp interface(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 .
Disease
Prevention of Renal Damage: Intravascular hemolysis 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
Hp has developed of a lot interest in drug therapy development recently because of its effectiveness in detoxifying free Hb activity when hemolytic related events occur in diseases [16][39][40][41] such as sickle cell anemia [16].
Research Interests
Ololade Fatunmbi (Graduate Assistant Researcher)
Studies of the Hp mediated Hb clearance pathway suggest that Hp may be used for targeted drug delivery (1). This use requires a detailed understanding of conformational dynamics and interactions in this protein/receptor system. However, Hb∙Hp/CD163 complex crystal structure and conformational dynamics have not yet been determined. I focus on studyingatomic level predictions of Hb∙Hp/CD163 protein interactions and conformational dynamics using bioinformatics techniques and native mass spectrometry (MS).
Chibueze Egeruoh (Undergraduate Researcher)
African trypanosomiasis or sleeping sickness is a parasitic disease of humans and other animals. On the structure of African trypanosomes, there is a coat of surface monolayer of variant surface glycoprotein (VSG) that protects the parasite. Within the VSG coat there are HbHp receptors that have the purposes of binding Hb-Hp acquisition heme through endocytosis so that the parasite would have nutrients such as iron fdfound within the heme. Understanding the interaction of Hb-Hp complexes and trypanosome receptors with improve drug delivery to the atrypanosomes. I conduct molecular modeling studies on trypanosome receptors and docking studied of Hb-Hp trypanosome receptors in complex with Hb-Hp complexes .
References
Ololade Fatunmbi and Chibueze Egeruoh. 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.
