Please note these web pages are part of an assignment for a graduate course in Advanced Biochemistry and Molecular Biology BCMB8010 at the University of Georgia. Questions should be directed to Abigail Cline (aecline@uga.edu)

Transferrin

A β globulin in blood plasma that combines with and transports iron

Introduction (Abstract)

Iron is a biologically essential metal for its role in hemoglobin synthesis of erythrocytes, oxidation-reduction reactions, and cell proliferation. Too much iron accumulation can be toxic because free iron can react with peroxides to produce free radicals, resulting in organ dysfunction and hemochromatosis (1). Too little iron causes a G(1)/ S arrest and can lead to apoptosis because of iron’s role in cell cycle control. Therefore, iron is tightly regulated in mammals and is transported by a specific carrier protein, transferrin (2). Transferrin is a major glycoprotein found in the blood that carries iron from the liver and the intestine to tissue cells. The iron-free form, apotransferrin, has two iron binding sites that bind Fe³⁺ ions to then form ferrotransferrin (3). Transferrin is a single chain that is arranged in two lobes, each lobe then consisting of two dissimilar domains that surround a hydrophilic cleft bearing an iron binding site. The domains are connected by two antiparallel strands, which along with the domains contribute a ligand to the iron binding site. The two lobes are then fastened together by a connecting strand of six to eight residues. Between the two lobes there is greater than 60% sequence identity, which is evidence that transferrin may have arisen from a gene duplication and fusion event (4).

Transferrin takes an “open-jaw” conformation when not bound to iron due to its domains being separated. When iron binds, the domains undergo a rigid rotation to guard the bound iron from hydrolysis and release. The iron binding is dependent on the binding of a synergistic anion, normally carbonate. Protonation of this anion results in its expulsion from the protein, which is a critical step in iron release (4). Cells replenish their iron stores by taking up transferrin bound to its receptor in a process known as clathrin-meditated endocytosis (3). Transferrin first binds to its paired receptor on the cell’s surface, and then is internalized into an endosomal vesicle. Vesicular membrane proteins then pump protons that cause acidification of these endosomes, resulting in a drop in pH from 7.4 to 5.5 within the vesicle, facilitating the release of iron from transferrin. Iron is then transferred across the vesicular membrane into the cytoplasm where it is stored by ferritin or used to meet the needs of the cell. Apotransferrin remains bound to the transferrin receptor and this complex recycles to the cell surface. Upon exposure to normal pH, apotransferrin dissociates from the receptor and goes on to bind more iron (3, 5). 

 Cancer cells have been found to have increased transferrin levels because of the cells’ iron requirements for cellular proliferation (6). Transferrin saturation of more than 60% has been identified as a cancer risk, especially when coupled with a high dietary iron intake. Therefore a more complete knowledge of the molecular mechanisms of iron and transferrin is essential for understanding the cell cycle (7).

***All references cited in this abstract will be given in the full enzyme report.

BCMB8010 web page Enzyme Report Powerpoint Presentation