Characterization of the l-ferritin variant 460InsA responsible of a hereditary ferritinopathy disorder.
Hereditary ferritinopathies are dominant inherited movement disorders associated with extensive alterations of the l-ferritin C-terminus peptide caused by nucleotide insertions in l-ferritin gene (FTL). We describe the characterization of the most common variant, produced by the 460InsA mutations and here named Ln1. The recombinant Ln1 assembled into 24-mer ferritin shells with low efficiency, however, it was able to form heteropolymers that showed a reduced capacity to incorporate iron in vitro. The Ln1 expressed in HeLa cells formed hybrid ferritins, with the endogenous H and L chains, and caused an iron excess phenotype. Ferritin inactivation and faster degradation in Ln1 transfectants concurred in increasing iron availability, which was probably responsible for the higher sensitivity to H(2)O(2) toxicity and higher level of oxidized proteins. The findings suggest that the pathogenic effects of Ln1 expression are more likely due to deregulation of cellular iron homeostasis rather than to protein conformational problems.
Cozzi
Anna
A
San Raffaele Scientific Institute, DIBIT, 20132 Milan, Italy.
Santambrogio
Paolo
P
Corsi
Barbara
B
Campanella
Alessandro
A
Arosio
Paolo
P
Levi
Sonia
S
D002490:Central Nervous System / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D015536:Down-Regulation / Q000502:physiology; D005293:Ferritins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D020868:Gene Silencing / Q000502:physiology; D006367:HeLa Cells; D006706:Homeostasis / Q000187:drug effects / Q000502:physiology; D006801:Humans; D006861:Hydrogen Peroxide / Q000633:toxicity; D007501:Iron / Q000378:metabolism; D019189:Iron Metabolism Disorders / Q000235:genetics* / Q000378:metabolism* / Q000503:physiopathology; D009154:Mutation / Q000235:genetics*; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology; D010455:Peptides / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D011108:Polymers / Q000378:metabolism; D011487:Protein Conformation / Q000187:drug effects; D034622:RNA Interference / Q000502:physiology; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism
D010455:Peptides; D011108:Polymers; D011993:Recombinant Fusion Proteins; D005293:Ferritins; D006861:Hydrogen Peroxide; D007501:Iron