Investigation of the Iron(II) Release Mechanism of Human H-Ferritin as a Function of pH

Sala, Davide; Ciambellotti, Silvia; Giachetti, Andrea; Turano, Paola; Rosato, Antonio

doi:10.1021/acs.jcim.7b00306

Cited by 25 publications

(13 citation statements)

References 26 publications

(38 reference statements)

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“…These changes in function may be due to a decreased capacity of the mutant nanocage to mineralize and retain iron at the protein core due to the disruption of the 4FP. Other studies have shown that changes in pH compromise FtH homopolymer's function retaining iron in the mineralized core 25 , highlighting the importance of pH in the functionality of ferritin relatively to the uptake of iron and its mineralization. The main exit of iron from the ferritin mineral core is believed to involve ferritin degradation in the lysosome 26 , where ferritin is transferred in a highly regulated process known as ferritinophagy 27 .…”

Section: Resultsmentioning

confidence: 99%

Cryo-EM structures and functional characterization of homo- and heteropolymers of human ferritin variants

Irimia-Dominguez

Sun

et al. 2020

Sci Rep

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The role of abnormal brain iron metabolism in neurodegenerative diseases is still insufficiently understood. Here, we investigate the molecular basis of the neurodegenerative disease hereditary ferritinopathy (HF), in which dysregulation of brain iron homeostasis is the primary cause of neurodegeneration. We mutagenized ferritin’s three-fold pores (3FPs), i.e. the main entry route for iron, to investigate ferritin’s iron management when iron must traverse the protein shell through the disrupted four-fold pores (4FPs) generated by mutations in the ferritin light chain (FtL) gene in HF. We assessed the structure and properties of ferritins using cryo-electron microscopy and a range of functional analyses in vitro. Loss of 3FP function did not alter ferritin structure but led to a decrease in protein solubility and iron storage. Abnormal 4FPs acted as alternate routes for iron entry and exit in the absence of functional 3FPs, further reducing ferritin iron-storage capacity. Importantly, even a small number of MtFtL subunits significantly compromises ferritin solubility and function, providing a rationale for the presence of ferritin aggregates in cell types expressing different levels of FtLs in patients with HF. These findings led us to discuss whether modifying pores could be used as a pharmacological target in HF.

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Section: Resultsmentioning

confidence: 99%

Cryo-EM structures and functional characterization of homo- and heteropolymers of human ferritin variants

Irimia-Dominguez

Sun

et al. 2020

Sci Rep

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“…By freezing ferritin crystals at different time intervals after exposure to a ferrous salt, it was possible to identify the iron binding ligands in the ferroxidase site (that were fully consistent with the NMR results) and to draw the path along which iron(II) ions move to reach the ferroxidase site , , , . The driving force for the observed intra‐cage iron trafficking has been analyzed by studies on a series of protein variants obtained by site directed mutagenesis that were investigated by integrating structural data, computational approaches, and kinetic measurements of the efficiency of ferroxidase and biomineralization activities , …”

Section: Iron Pathways Through the Ferritin Cagesmentioning

confidence: 99%

Structural Biology of Iron‐Binding Proteins by NMR Spectroscopy

Ciambellotti

Turano

2019

Eur J Inorg Chem

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Herein we provide an overview of the NMR strategies that have been designed in our lab to contribute answering some basic questions in inorganic structural biology, spanning from the initial exploitation of paramagnetic NMR constraints for the determination of the structural and dynamic properties of small isolated metalloproteins, to the study of ultra-weak [a] Resonance research activities include development and application of NMR spectroscopic approaches to metalloproteins and their complexes. Silvia Ciambellotti earned her degree in Molecular Biotechnologies (2013) and received a PhD in Structural Biology (2016) from the University of Florence under the supervision of Professor Paola Turano. Currently she is a post-doctoral fellow at the same University. Her studies mainly focus on the structural and functional characterization of the human ferritin family and their possible application for nanodelivery.

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“…Thus, it was important to compute the protonation state of titratable groups at pH 4 and pH 9; this was done using the H++ server . The AMBER package was used for molecular dynamics (MD) simulations; details on the MD setup are given in Sala et al…”

Section: Molecular Dynamics Studies On Metal Storage and Transportmentioning

confidence: 99%

Application of Molecular Dynamics to the Investigation of Metalloproteins Involved in Metal Homeostasis

2018

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Available estimates indicate that 30-40 % of all proteins need at least one metal ion to perform their biological function. Therefore, they are called metalloproteins. The correct biosynthesis of metalloproteins requires living organisms to be able to cope with issues such as the limited bioavailability or the potential cytotoxicity of several essential metals. Thus, organisms have developed complex machineries that guarantee the proper intracellular concentration and distribution among compartments of each metal, i.e. metal homeostasis. To understand how the different proteins responsible for metal homeostasis carry out their function, it is necessary to investigate their three-dimensional (3D) structure and mobility at the atomic [a] Magnetic respectively. Metalloproteins are the main focus of his research activities. Antonio Rosato has developed innovative methodologies for the study via NMR of the solution structure of paramagnetic metalloproteins. He is actively working on molecular dynamics and on the implementation of bioinformatics research of these systems. He co-authored about 110 articles in international scientific journals and has contributed to the determination of the structure in solution of around thirty metalloproteins.

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Investigation of the Iron(II) Release Mechanism of Human H-Ferritin as a Function of pH

Cited by 25 publications

References 26 publications

Cryo-EM structures and functional characterization of homo- and heteropolymers of human ferritin variants

Cryo-EM structures and functional characterization of homo- and heteropolymers of human ferritin variants

Structural Biology of Iron‐Binding Proteins by NMR Spectroscopy

Application of Molecular Dynamics to the Investigation of Metalloproteins Involved in Metal Homeostasis

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