NDLI: Evidence that His349 acts as a pH-inducible switch to accelerate receptor-mediated iron release from the C-lobe of human transferrin

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Evidence that His349 acts as a pH-inducible switch to accelerate receptor-mediated iron release from the C-lobe of human transferrin

Content Provider	World Health Organization (WHO)-Global Index Medicus
Author	Steere, Ashley N. Byrne, Shaina L. Chasteen, N. Dennis Smith, Valerie C. MacGillivray, Ross T. A. Mason, Anne B.
Description	Country affiliation: United States Author Affiliation: Steere AN ( Department of Biochemistry, College of Medicine, University of Vermont, 89 Beaumont Avenue, Burlington, VT 05405-0068, USA.)
Abstract	His349 in human transferrin (hTF) is a residue critical to transferrin receptor (TFR)-stimulated iron release from the C-lobe. To evaluate the importance of His349 on the TFR interaction, it was replaced by alanine, aspartate, lysine, leucine, tryptophan, and tyrosine in a monoferric C-lobe hTF construct $(Fe_{C}hTF).$ Using a stop-ped-flow spectrofluorimeter, we determined rate processes assigned to iron release and conformational events (in the presence and in the absence of the TFR). Significantly, all mutant/TFR complexes feature dampened iron release rates. The critical contribution of His349 is most convincingly revealed by analysis of the kinetics as a function of pH (5.6–6.2). The $Fe_{C}hTF/TFR$ complex titrates with a $pK_{a}$ of approximately 5.9. By contrast, the H349A mutant/TFR complex releases iron at higher pH with a profile that is almost the inverse of that of the control complex. At the putative endosomal pH of 5.6 (in the presence of salt and chelator), iron is released from the H349W mutant/TFR and H349Y mutant/TFR complexes with a single rate constant similar to the iron release rate constant for the control; this suggests that these substitutions bypass the required pH-induced conformational change allowing the C-lobe to directly interact with the TFR to release iron. The H349K mutant proves that although the positive charge is crucial to complete iron release, the geometry at this position is also critical. The H349D mutant shows that a negative charge precludes complete iron release at pH 5.6 both in the presence and in the absence of the TFR. Thus, histidine uniquely drives the pH-induced conformational change in the C-lobe required for TFR interaction, which in turn promotes iron release.
File Format	HTM / HTML
ISSN	09498257
e-ISSN	14321327
DOI	10.1007/s00775-010-0694-2
Journal	JBIC Journal of Biological Inorganic Chemistry
Issue Number	8
Volume Number	15
Language	English
Publisher	Springer
Publisher Date	2010-11-01
Publisher Place	Germany
Access Restriction	Open
Subject Keyword	Discipline Biochemistry Histidine Chemistry Receptors, Transferrin Transferrin Genetics Metabolism Hydrogen-ion Concentration Kinetics Protein Binding Protein Conformation Research Support, N.i.h., Extramural
Content Type	Text
Resource Type	Article
Subject	Biochemistry Inorganic Chemistry

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Evidence that His349 acts as a pH-inducible switch to accelerate receptor-mediated iron release from the C-lobe of human transferrin

Evidence that His349 acts as a pH-inducible switch to accelerate receptor-mediated iron release from the C-lobe of human transferrin

How the binding of human transferrin primes the transferrin receptor potentiating iron release at endosomal pH.

Incorporation of 5-hydroxytryptophan into transferrin and its receptor allows assignment of the pH induced changes in intrinsic fluorescence when iron is released.

Human serum transferrin: a tale of two lobes. Urea gel and steady state fluorescence analysis of recombinant transferrins as a function of pH, time, and the soluble portion of the transferrin receptor.

The pH dependence of heme pocket hydration and ligand rebinding kinetics in photodissociated carbonmonoxymyoglobin.

Detailed molecular dynamics simulations of human transferrin provide insights into iron release dynamics at serum and endosomal pH.

Protonation and Anion Binding Control the Kinetics of Iron Release from Human Transferrin

Scope and utility of hydrogen exchange as a tool for mapping landscapes.

Evidence that His349 acts as a pH-inducible switch to accelerate receptor-mediated iron release from the C-lobe of human transferrin

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