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Biology and receptor interactions of P97 and the transferrin receptors Walker, Brandie Laurel


Melanotransferrin, or p97, is an iron binding protein that is expressed as both a glycosylphosphatidylinositol-anchored form and as a soluble form. While the anchored form internalizes iron, the function of the soluble form is still unknown. Soluble p97 levels are increased in the serum and cerebral spinal fluid of Alzheimer disease patients, but the reasons for this increase are undetermined. In order to begin to address the question of function for this soluble protein, possible receptor interactions were studied. The interaction of p97 and transferrin receptor 1 was characterized with radioligand assays and immunofluorescent labeling assays. These experiments demonstrated that p97 interacts with the transferrin receptor 1 in cell binding experiments. However, p97 was not able to deliver iron into the cells via transferrin receptor 1. Furthermore, BIAcore studies were not able to measure any interaction between p97 and transferrin receptor 1. In the search for other likely candidate receptors of p97, a novel homologue of the transferrin receptor 1 was discovered through mining of the EST database. Expression of this protein was revealed by Northern blot to be largely restricted to the liver. In embryogenesis, the mouse transferrin receptor 2 is present by E15 and continues to increase in expression through E17, in contrast to transferrin receptor 1 that is discernable by E7, increases until E l5 and decreases by E 17 . Transferrin receptor 2 is present on the brain endothelial cells that form the blood-brain barrier implicating it as a candidate receptor for transport of p97 (and iron) into or out of the brain. Interestingly, in transfected cells that over express both transferrin receptor 1 and 2, the receptor is present at the cell surface as a heterodimeric combination of the two receptors. p97 binds to the mouse transferrin receptor 2, and unlike transferrin receptor 1, also facilitates the uptake of 5 5Fe through this interaction. Thus, in addition to receptor binding, the functional aspect of this interaction can be demonstrated. Clearly, identification of transferrin receptor 2 as a receptor of p97 is only one of the first important steps toward the ultimate goal of clarifying the function of soluble p97.

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