9z91 | pdb_00009z91
Human Ferritin Heavy Chain in the presence of Mg-ATP
Structural highlights
FunctionFRIH_HUMAN Stores iron in a soluble, non-toxic, readily available form. Important for iron homeostasis. Has ferroxidase activity. Iron is taken up in the ferrous form and deposited as ferric hydroxides after oxidation. Also plays a role in delivery of iron to cells. Mediates iron uptake in capsule cells of the developing kidney (By similarity). Publication Abstract from PubMedFerritin safeguards cells from iron-induced oxidative stress by oxidizing and storing Fe(2+) within its nanocage, yet how its macromolecular architecture enables responsiveness to the cellular chemical environment remains unclear. Here, we show that ferritin's iron-oxidation activity is modulated by an electrostatic gating mechanism centered at its 3-fold channels and sensitive to solution charge conditions representative of intracellular metabolites. At physiologically relevant nucleotide concentrations, ferritin-catalyzed Fe(2+) oxidation is strongly attenuated in the presence of triphosphate nucleotides, while diphosphates and monophosphates exert progressively weaker effects, indicating that ferritin responds selectively to the charge density and geometry of the phosphate chain, rather than nucleotide identity. High-resolution cryo-electron microscopy identifies condition-dependent differences in non-protein density within and near the ferritin 3-fold channels, consistent with changes in the local solvent and/or ion environment, rather than discrete ligand binding. Fluorescence and calorimetric measurements reveal weak, reversible nucleotide association (K(D) approximately 1 mM), supporting a low-affinity, dynamic electrostatic interaction mode. The inhibitory trend persists under reduced oxygen conditions and across ferritin assemblies with varying H/L composition, supporting physiological relevance across cellular oxygen tensions and native ferritin heteropolymers. Ferritin activity is similarly modulated in bacterial, yeast, and human cell lysates under near-physiological conditions, demonstrating the robustness of this behavior in complex environments. Together, these findings establish ferritin as a biological macromolecule whose intrinsic channel electrostatics enable reversible modulation of iron uptake and oxidation in response to its chemical environment. Ferritin iron uptake and oxidation are dynamically modulated by nucleotide phosphate architecture via electrostatic gating.,Rajendran A, Henley S, Nannenga BL, Terashi G, Srivastava A, Kihara D, Bou-Abdallah F Int J Biol Macromol. 2026 Mar;352:151118. doi: 10.1016/j.ijbiomac.2026.151118. , Epub 2026 Feb 26. PMID:41763418[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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