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|3hx7, resolution 2.85Å ()|
|Gene:||FTL (Homo sapiens)|
Crystal structure of human ferritin Phe167SerfsX26 mutant. This file is a part 3/3 of the split entry and contains the copies 5 and 6 of the total six copies of the biological unit that are present in the crystallographic asymmetric unit. The entire structure contains six copies of the biological unit in the crystallographic asymmetric unit and is described in remark 400
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 with mutant ferritin. Even without competition, the amount of iron incorporation over the first few minutes differed severalfold. Our data suggest that disruption at the 4-fold pores may lead to direct iron mishandling through attenuated iron incorporation by the soluble form of mutant ferritin and that the disordered C-terminal polypeptides may play a major role in iron-induced precipitation and formation of ferritin inclusion bodies in hereditary ferritinopathy.
Unraveling of the E-helices and disruption of 4-fold pores are associated with iron mishandling in a mutant ferritin causing neurodegeneration., Baraibar MA, Muhoberac BB, Garringer HJ, Hurley TD, Vidal R, J Biol Chem. 2010 Jan 15;285(3):1950-6. Epub 2009 Nov 18. PMID:19923220
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
[Q6S4P3_HUMAN] Stores iron in a soluble, non-toxic, readily available form. Important for iron homeostasis (By similarity).[RuleBase:RU000622]
About this Structure
- Baraibar MA, Muhoberac BB, Garringer HJ, Hurley TD, Vidal R. Unraveling of the E-helices and disruption of 4-fold pores are associated with iron mishandling in a mutant ferritin causing neurodegeneration. J Biol Chem. 2010 Jan 15;285(3):1950-6. Epub 2009 Nov 18. PMID:19923220 doi:10.1074/jbc.M109.042986
- Baraibar MA, Barbeito AG, Muhoberac BB, Vidal R. Iron-mediated aggregation and a localized structural change characterize ferritin from a mutant light chain polypeptide that causes neurodegeneration. J Biol Chem. 2008 Nov 14;283(46):31679-89. Epub 2008 Aug 28. PMID:18755684 doi:10.1074/jbc.M805532200