A Molecular Explanation For Iron Overload Disease

A Molecular Explanation For Iron Overload Disease

Feb 17, 2009 2:07 PM

SALT LAKE CITY - University of Utah School of Medicine researchers have found a mechanistic explanation for the dominant inheritance pattern for hepcidin-resistant hemochromatosis, a disease of iron overload, according to a study published in the early online edition of the Proceedings of the National Academy of Sciences for the week of Feb. 16-20, 2009.

Iron balance within the body is regulated by the interaction between a liver-produced hormone called hepcidin and the iron transporter ferroportin. Hepcidin binds to ferroportin resulting in the addition of a phosphate group to ferroportin, a process called phosphorylation. Phosphorylation is critical step in the degradation of the iron transporter and the subsequent decrease in iron export out of cells.  The inability to respond to hepcidin causes a buildup of iron that is damaging to body organs, a condition known as hepcidin-resistant iron overload.

"In this study, we were able to confirm that the protein responsible for phosphorylation of ferroportin is an enzyme called Janus kinase 2 (Jak2)," said senior author Jerry Kaplan, Ph.D., professor of pathology and assistant vice president for research at the University of Utah Health Sciences.

Hepcidin is secreted in response to both increased levels of iron in the blood and inflammation. Kaplan and his colleagues determined that the binding of hepcidin to ferroportin was required for Jak2 to bind to the iron transporter. They also found that the binding and activation of Jak2 induced the phosphorylation of ferroportin, leading to the internalization of the iron transporter and its degradation inside the cell.
Individuals with hepcidin-resistant iron overload have mutations in ferroportin that result in an inability to respond to adequate levels of hepcidin. Ferroportin consists of two identical subunits that are held together by intramolecular forces. Kaplan and his colleagues discovered that hepcidin must bind to both subunits of ferroportin for Jak2 to bind to ferroportin. This new insight demonstrates that Jak2 binding requires a functional hepcidin binding site on each ferroportin subunit.

"The highly cooperative nature of Jak2 activation provides a molecular explanation for the dominant transmission of hepcidin-resistance iron overload disease," said Kaplan.
Hepcidin-resistant iron overload, or ferroportin disease, is passed on with a dominant inheritance pattern, meaning that if one of two parents is affected by this disease, every child has a one-in-two chance of also being affected. As suggested by the findings of Kaplan and his colleagues, the highly cooperative interactions among hepcidin, ferroportin, and Jak2 provide a clearer understanding of the mechanism behind the genetic transmission of ferroportin disease.

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