Structure-based mutagenesis reveals critical residues in the transferrin receptor participating in the mechanism of pH-induced release of iron from human serum transferrin.

Biochemistry
Ashley N SteereAnne B Mason

Abstract

The recent crystal structure of two monoferric human serum transferrin (Fe(N)hTF) molecules bound to the soluble portion of the homodimeric transferrin receptor (sTFR) has provided new details about this binding interaction that dictates the delivery of iron to cells. Specifically, substantial rearrangements in the homodimer interface of the sTFR occur as a result of the binding of the two Fe(N)hTF molecules. Mutagenesis of selected residues in the sTFR highlighted in the structure was undertaken to evaluate the effect on function. Elimination of Ca(2+) binding in the sTFR by mutating two of four coordinating residues ([E465A,E468A]) results in low production of an unstable and aggregated sTFR. Mutagenesis of two histidines ([H475A,H684A]) at the dimer interface had little effect on the kinetics of release of iron at pH 5.6 from either lobe, reflecting the inaccessibility of this cluster to solvent. Creation of an H318A sTFR mutant allows assignment of a small pH-dependent initial decrease in the magnitude of the fluorescence signal to His318. Removal of the four C-terminal residues of the sTFR, Asp757-Asn758-Glu759-Phe760, eliminates pH-stimulated release of iron from the C-lobe of the Fe(2)hTF/sTFR Δ757-760 complex. The inabi...Continue Reading

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Citations

Apr 8, 2014·Journal of Inorganic Biochemistry·Tyson TerpstraFadi Bou-Abdallah
Apr 10, 2015·Chemical Communications : Chem Comm·Minji WangHongzhe Sun
Dec 30, 2014·Journal of Biological Inorganic Chemistry : JBIC : a Publication of the Society of Biological Inorganic Chemistry·Guinevere MathiesEdgar J J Groenen
Jun 1, 2018·Annual Review of Nutrition·Marianne Wessling-Resnick
Sep 1, 2018·Protein Science : a Publication of the Protein Society·Jakub PtacekCyril Barinka
Aug 4, 2019·Progress in Neurobiology·Kasper Bendix JohnsenTorben Moos
Apr 12, 2019·ACS Chemical Biology·Aviva Levina, Peter A Lay

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