Structure of human ferritin L chain

Abstract

Ferritin is the major iron-storage protein present in all cells. It generally contains 24 subunits, with different ratios of heavy chain (H) to light chain (L), in the shape of a hollow sphere hosting up to 4500 ferric Fe atoms inside. H-rich ferritins catalyse the oxidation of iron(II), while L-rich ferritins promote the nucleation and storage of iron(III). Several X-ray structures have been determined, including those of L-chain ferritins from horse spleen (HoSF), recombinant L-chain ferritins from horse (HoLF), mouse (MoLF) and bullfrog (BfLF) as well as recombinant human H-chain ferritin (HuHF). Here, structures have been determined of two crystal forms of recombinant human L-chain ferritin (HuLF) obtained from native and perdeuterated proteins. The structures show a cluster of acidic residues at the ferrihydrite nucleation site and at the iron channel along the threefold axis. An ordered Cd2+ structure is observed within the iron channel, offering further insight into the route and mechanism of iron transport into the capsid. The loop between helices D and E, which is disordered in many other L-chain structures, is clearly visible in these two structures. The crystals generated from perdeuterated HuLF will be used for neutron diffraction studies.

Iron-mediated Aggregation and a Localized Structural Change Characterize Ferritin from a Mutant Light Chain Polypeptide That Causes Neurodegeneration

“…For comparison, FTH1 homopolymers are less stable to heat denaturation than FTL homopolymers, perhaps because of residues located at the intersubunit contacts along the 3-and 4-fold channels and by salt bridges within the 4-helix bundles themselves between Lys-62 and Glu-107 (24,32). Indeed, native E helix conformation appears to help stabilize the subunit structure of the FTL homopolymer by making several hydrophobic contacts with apolar side chains near the start of helix B and the end of D as well as being linked by hydrogen bonds to the N-terminal ends of helices B and C (2,6,7,39). Given the spectroscopic results, the difference in thermal stability observed between the WT and mutant homopolymers can be attributed to the loss of the interactions around the E helix in the MT-FTL subunit.…”

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

“…Structure Determination-The structure was solved by molecular replacement using the program MOLREP with the atomic coordinates of human L-chain ferritin subunit (35) (Protein Data Bank code 2ffx). Model building and refinements were performed using the programs COOT (36) and REF-MAC5 (37) iteratively.…”

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

“…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.…”