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Iron and bismuth bound human serum transferrin reveals a partially-opened conformation in the N-lobe.

ABSTRACT: Human serum transferrin (hTF) binds Fe(III) tightly but reversibly, and delivers it to cells via a receptor-mediated endocytosis process. The metal-binding and release result in significant conformational changes of the protein. Here, we report the crystal structures of diferric-hTF (Fe(N)Fe(C)-hTF) and bismuth-bound hTF (Bi(N)Fe(C)-hTF) at 2.8 and 2.4 Å resolutions respectively. Notably, the N-lobes of both structures exhibit unique "partially-opened" conformations between those of the apo-hTF and holo-hTF. Fe(III) and Bi(III) in the N-lobe coordinate to, besides anions, only two (Tyr95 and Tyr188) and one (Tyr188) tyrosine residues, respectively, in contrast to four residues in the holo-hTF. The C-lobe of both structures are fully closed with iron coordinating to four residues and a carbonate. The structures of hTF observed here represent key conformers captured in the dynamic nature of the transferrin family proteins and provide a structural basis for understanding the mechanism of metal uptake and release in transferrin families.

SUBMITTER: Yang N

PROVIDER: S-EPMC3525939 | biostudies-literature | 2012

REPOSITORIES: biostudies-literature

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Iron and bismuth bound human serum transferrin reveals a partially-opened conformation in the N-lobe.

Yang Nan N Zhang Hongmin H Zhang Hongmin H Wang Minji M Hao Quan Q Sun Hongzhe H

Scientific reports 20121219

Human serum transferrin (hTF) binds Fe(III) tightly but reversibly, and delivers it to cells via a receptor-mediated endocytosis process. The metal-binding and release result in significant conformational changes of the protein. Here, we report the crystal structures of diferric-hTF (Fe(N)Fe(C)-hTF) and bismuth-bound hTF (Bi(N)Fe(C)-hTF) at 2.8 and 2.4 Å resolutions respectively. Notably, the N-lobes of both structures exhibit unique "partially-opened" conformations between those of the apo-hTF ...[more]

PMID: 23256035

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Project description:Background:Iron deficiency anemia (IDA) is a widespread nutritional deficiency, and iron supplementation, especially with ferrous sulfate (FeSO4), is the most common strategy to treat IDA; however, compliance is often poor with daily FeSO4 owing to negative side effects. In a previous study, iron from iron-enriched Aspergillus oryzae [Ultimine® Koji Iron (ULT)] was absorbed similarly to FeSO4. Objectives:The main objective of this study was to assess the safety of consuming ULT in terms of increasing non-transferrin-bound iron (NTBI) and gastrointestinal distress. Methods:Young female participants (n = 16) with serum ferritin <40 ?g/L were randomly assigned to a double-blind, 9-wk crossover study with a 3-wk placebo/washout period between treatments. Oral FeSO 4 and ULT supplements containing 65 mg Fe were administered daily for 21 consecutive days. On day 1, serum iron (SI), percentage transferrin saturation (%TS), and NTBI were measured for 8 h on the first day of iron consumption. Changes in biochemical indicators were evaluated after 3 wk consumption. Side effects questionnaires were completed weekly on 2 randomly selected weekdays and 1 weekend day for the entire study. Results:SI, %TS, and NTBI were all markedly higher during hours 2-8 (P < 0.001) with FeSO4 than with ULT. Oxidative stress, inflammatory, and kidney and liver function markers remained unchanged with both supplementations compared with placebo. Changes in iron status markers were not significantly different among the 3 treatments. Individual or global side effects were not significantly different among all treatments. Even when common side effects of nausea, constipation, and diarrhea were combined, FeSO4 treatment had a significantly higher effect than ULT (P = 0.04) and placebo (P = 0.004) only at week 3, but the difference was not significant between ULT and placebo. Conclusions:Low NTBI production and fewer common gastrointestinal side effects with ULT suggest that it is a safe oral iron supplement to treat IDA. This trial was registered at clinicaltrials.gov as NCT04018300.

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Iron and bismuth bound human serum transferrin reveals a partially-opened conformation in the N-lobe.

Publications

Iron and bismuth bound human serum transferrin reveals a partially-opened conformation in the N-lobe.

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