Mutant Ferritin L-chains That Cause Neurodegeneration Act in a Dominant-negative Manner to Reduce Ferritin Iron Incorporation

Luscieti, Sara; Santambrogio, Paolo; d’Estaintot, Béatrice Langlois; Granier, T.; Cozzi, Anna; Poli, Maura; Gallois, B.; Finazzi, Dario; Cattaneo, Angela; Levi, Sonia; Arosio, Paolo

doi:10.1074/jbc.m109.096404

Cited by 48 publications

(57 citation statements)

References 46 publications

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“…It is tempting to speculate that the low complex III activity in our patient also affects neuronal intramitochondrial iron handling, promoting further brain oxidative damage, abnormal protein aggregation, 2 and neuronal cell death. 6 …”

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confidence: 97%

De novo FTL mutation: A clinical, neuroimaging, and molecular study

et al. 2012

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confidence: 97%

De novo FTL mutation: A clinical, neuroimaging, and molecular study

et al. 2012

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“…Interestingly, this occurs also in vitro, and despite the evidence that L-chain homopolymers have a higher stability than the H-chain ones, when the two chains are renatured together they form heteropolymers in which the ratio between the two subunits is dictated only by their availability. Thus, it is possible to produce ferritin shells ranging from L 24 H 0 to L 0 H 24 with all the intermediates (12,13). The mechanism of this reaction of assembly and how the two subunits preferentially interact to form the hybrid 24-mer is unclear.…”

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confidence: 99%

Study of ferritin self-assembly and heteropolymer formation by the use of Fluorescence Resonance Energy Transfer (FRET) technology

Carmona

Poli

Bertuzzi

et al. 2017

Biochimica et Biophysica Acta (BBA) - General Subjects

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Background: The high stability and strong self-assembly properties made ferritins the most used proteins for nanotechnological applications. Human ferritins are made of 24 subunits of the H-and Ltype that coassemble in an almost spherical nanocage 12 nm across, delimiting a large cavity. The mechanism and kinetics of ferritin self-assembly and why H/L heteropolymers formation is favored over the homopolymers remain unclarified. Methods: We used the Fluorescence Resonance Energy Transfer (FRET) by binding multiple donor or acceptor Alexa Fluor fluorophores on the outer surface of human H and L ferritins and then denaturing and reassembling them in different proportions and conditions. Results: The FRET-efficiency increase from <0.3 of the disassembled to >0.7 in the reassembled allowed to study the self-assembly kinetics. We found that their assembly was complete in about one hour, and that the initial rate of self-assembly of H/L heteropolymers was slightly faster than that of the H/H homopolymers. Then, by adding various proportions of unlabeled H or L-chains to the FRET system we found that the presence of the L-chains displaced the formation of H-H dimers more efficiently than that of the H-chains. Conclusion: Heterodimeric (H/L) subunit association is preferred during H/L heteropolymers formation. The H-chains arrange at distant positions on the heteropolymeric shell until they reach a number above eight, when they start to co-localize and the ferroxidase activity of the heteropolymer reaches a plateau. General significance: This favored formation of H/L heterodimers, which is the initial step in ferritin self-assembly, contributes to explain the preferred formation of H/L heteropolymers over the H or L homopolymers. Keywords

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“…1B) for an efficient biomineralization was inferred by site-directed mutagenesis or chemical modifications (8,9). Nonphysiological metal ions like Cd 2+ have been observed bound to the corresponding glutamates of the above-mentioned human Glu residues in several mammalian L-ferritins (10)(11)(12)(13)(14) whereas the structure with iron of these homopolymeric L-ferritins has not yet been reported.…”

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Chemistry at the protein–mineral interface in L-ferritin assists the assembly of a functional (μ ³ -oxo)Tris[(μ ² -peroxo)] triiron(III) cluster

Pozzi

Ciambellotti

Bernacchioni

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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X-ray structures of homopolymeric L-ferritin obtained by freezing protein crystals at increasing exposure times to a ferrous solution showed the progressive formation of a triiron cluster on the inner cage surface of each subunit. After 60 min exposure, a fully assembled (μ 3 -oxo)Tris[(μ 2 -peroxo)(μ 2 -glutamato-κO:κO′)](glutamato-κO)(diaquo)triiron(III) anionic cluster appears in human L-ferritin. Glu60, Glu61, and Glu64 provide the anchoring of the cluster to the protein cage. Glu57 shuttles incoming iron ions toward the cluster. We observed a similar metallocluster in horse spleen L-ferritin, indicating that it represents a common feature of mammalian L-ferritins. The structures suggest a mechanism for iron mineral formation at the protein interface. The functional significance of the observed patch of carboxylate side chains and resulting metallocluster for biomineralization emerges from the lower iron oxidation rate measured in the E60AE61AE64A variant of human L-ferritin, leading to the proposal that the observed metallocluster corresponds to the suggested, but yet unobserved, nucleation site of L-ferritin.L-ferritin | metallocluster | nucleation site | biomineralization | X-ray

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Mutant Ferritin L-chains That Cause Neurodegeneration Act in a Dominant-negative Manner to Reduce Ferritin Iron Incorporation

Cited by 48 publications

References 46 publications

De novo FTL mutation: A clinical, neuroimaging, and molecular study

De novo FTL mutation: A clinical, neuroimaging, and molecular study

Study of ferritin self-assembly and heteropolymer formation by the use of Fluorescence Resonance Energy Transfer (FRET) technology

Chemistry at the protein–mineral interface in L-ferritin assists the assembly of a functional (μ ³ -oxo)Tris[(μ ² -peroxo)] triiron(III) cluster

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Mutant Ferritin L-chains That Cause Neurodegeneration Act in a Dominant-negative Manner to Reduce Ferritin Iron Incorporation

Cited by 48 publications

References 46 publications

De novo FTL mutation: A clinical, neuroimaging, and molecular study

De novo FTL mutation: A clinical, neuroimaging, and molecular study

Study of ferritin self-assembly and heteropolymer formation by the use of Fluorescence Resonance Energy Transfer (FRET) technology

Chemistry at the protein–mineral interface in L-ferritin assists the assembly of a functional (μ 3 -oxo)Tris[(μ 2 -peroxo)] triiron(III) cluster

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Product

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Chemistry at the protein–mineral interface in L-ferritin assists the assembly of a functional (μ ³ -oxo)Tris[(μ ² -peroxo)] triiron(III) cluster