title: The prion-ZIP connection: From cousins to partners in iron uptake.
abstract: Converging observations from disparate lines of inquiry are beginning to clarify the cause of brain iron dyshomeostasis in sporadic Creutzfeldt-Jakob disease (sCJD), a neurodegenerative condition associated with the conversion of prion protein (PrP(C)), a plasma membrane glycoprotein, from α-helical to a β-sheet rich PrP-scrapie (PrP(Sc)) isoform. Biochemical evidence indicates that PrP(C) facilitates cellular iron uptake by functioning as a membrane-bound ferrireductase (FR), an activity necessary for the transport of iron across biological membranes through metal transporters. An entirely different experimental approach reveals an evolutionary link between PrP(C) and the Zrt, Irt-like protein (ZIP) family, a group of proteins involved in the transport of zinc, iron, and manganese across the plasma membrane. Close physical proximity of PrP(C) with certain members of the ZIP family on the plasma membrane and increased uptake of extracellular iron by cells that co-express PrP(C) and ZIP14 suggest that PrP(C) functions as a FR partner for certain members of this family. The connection between PrP(C) and ZIP proteins therefore extends beyond common ancestry to that of functional cooperation. Here, we summarize evidence supporting the facilitative role of PrP(C) in cellular iron uptake, and implications of this activity on iron metabolism in sCJD brains.
authors.affiliation: a Department of Pathology ; School of Medicine; Case Western Reserve University ; Cleveland , OH USA.
authors.forename: Neena
authors.initials: N
authors.lastname: Singh
authors.affiliation: a Department of Pathology ; School of Medicine; Case Western Reserve University ; Cleveland , OH USA.
authors.forename: Abhishek
authors.initials: A
authors.lastname: Asthana
authors.affiliation: a Department of Pathology ; School of Medicine; Case Western Reserve University ; Cleveland , OH USA.
authors.forename: Shounak
authors.initials: S
authors.lastname: Baksi
authors.affiliation: a Department of Pathology ; School of Medicine; Case Western Reserve University ; Cleveland , OH USA.
authors.forename: Vilok
authors.initials: V
authors.lastname: Desai
authors.affiliation: a Department of Pathology ; School of Medicine; Case Western Reserve University ; Cleveland , OH USA.
authors.forename: Swati
authors.initials: S
authors.lastname: Haldar
authors.affiliation: a Department of Pathology ; School of Medicine; Case Western Reserve University ; Cleveland , OH USA.
authors.forename: Sahi
authors.initials: S
authors.lastname: Hari
authors.affiliation: a Department of Pathology ; School of Medicine; Case Western Reserve University ; Cleveland , OH USA.
authors.forename: Ajai K
authors.initials: AK
authors.lastname: Tripathi
mesh_terms: D000818:Animals; D027682:Cation Transport Proteins / Q000737:chemistry / Q000378:metabolism; D038181:FMN Reductase / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D007501:Iron / Q000378:metabolism*; D011328:Prions / Q000737:chemistry / Q000378:metabolism*; D020033:Protein Isoforms; D012097:Repressor Proteins / Q000737:chemistry / Q000378:metabolism*
chemical_list: D027682:Cation Transport Proteins; D011328:Prions; D020033:Protein Isoforms; D012097:Repressor Proteins; C497524:SLC39A14 protein, human; C549924:ZGPAT protein, human; D007501:Iron; D038181:FMN Reductase; C023903:ferric citrate iron reductase
keywords: Prion protein; ZIP proteins; ZIP14; ferrireductase; iron; sCJD