Unraveling of the E-helices and disruption of 4-fold pores are associated with iron mishandling in a mutant ferritin causing neurodegeneration.

The Journal of Biological Chemistry
Martin A BaraibarRuben Vidal

Abstract

Mutations in the coding sequence of the ferritin light chain (FTL) gene cause a neurodegenerative disease known as neuroferritinopathy or hereditary ferritinopathy, which is characterized by the presence of intracellular inclusion bodies containing the mutant FTL polypeptide and by abnormal accumulation of iron in the brain. Here, we describe the x-ray crystallographic structure and report functional studies of ferritin homopolymers formed from the mutant FTL polypeptide p.Phe167SerfsX26, which has a C terminus that is altered in amino acid sequence and length. The structure was determined and refined to 2.85 A resolution and was very similar to the wild type between residues Ile-5 and Arg-154. However, instead of the E-helices normally present in wild type ferritin, the C-terminal sequences of all 24 mutant subunits showed substantial amounts of disorder, leading to multiple C-terminal polypeptide conformations and a large disruption of the normally tiny 4-fold axis pores. Functional studies underscored the importance of the mutant C-terminal sequence in iron-induced precipitation and revealed iron mishandling by soluble mutant FTL homopolymers in that only wild type incorporated iron when in direct competition in solution wit...Continue Reading

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Citations

Aug 13, 2011·Journal of Neural Transmission·Erin K Stachowski, Robert Schwarcz
Feb 8, 2011·Journal of Neural Transmission·Esther G Meyron-HoltzLyora A Cohen
Mar 20, 2012·Neurobiology of Disease·Rainer ProhaskaRuth H Walker
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Sep 4, 2020·Experimental Biology and Medicine·Santosh R D'Mello, Mark C Kindy
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Jan 11, 2020·Frontiers in Neuroscience·Barry B Muhoberac, Ruben Vidal
Jan 14, 2021·Cellular and Molecular Life Sciences : CMLS·Anna CozziSonia Levi
Feb 22, 2012·Free Radical Biology & Medicine·Martin A BaraibarRuben Vidal

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