Tertiary structural changes and iron release from human serum transferrin

Human serum transferrin binds ferric ions with high affinity in the blood stream and releases them into cells by a process involving receptor-mediated endocytosis and a decrease in pH. The iron-release mechanism is unclear but protonation events and conformational changes are known to be important. In this study, we investigate properties of the iron-binding site theoretically. Our results suggest that an equatorial histidine could be in its histidinate form when bound to iron at neutral and high pH and that protonation of an axial tyrosine is a key event in iron release. Support for this mechanism from other metal-binding enzymes is also presented.

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Composition of pH-Sensitive Triad in C-Lobe of Human Serum Transferrin. Comparison to Sequences of Ovotransferrin and Lactoferrin Provides Insight into Functional Differences in Iron Release†

Biochemistry ◽

10.1021/bi0518693 ◽

2005 ◽

Vol 44 (47) ◽

pp. 15451-15460 ◽

Cited By ~ 26

Author(s):

Peter J. Halbrooks ◽

Anthony M. Giannetti ◽

Joshua S. Klein ◽

Pamela J. Björkman ◽

Julia R. Larouche ◽

...

Keyword(s):

Human Serum ◽

Ph Sensitive ◽

Serum Transferrin ◽

Iron Release ◽

Human Serum Transferrin ◽

Functional Differences ◽

Insight Into

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Intrinsic Fluorescence Reports a Global Conformational Change in the N-Lobe of Human Serum Transferrin following Iron Release†

Biochemistry ◽

10.1021/bi602425c ◽

2007 ◽

Vol 46 (37) ◽

pp. 10603-10611 ◽

Cited By ~ 28

Author(s):

Nicholas G. James ◽

Christopher L. Berger ◽

Shaina L. Byrne ◽

Valerie C. Smith ◽

Ross T. A. MacGillivray ◽

...

Keyword(s):

Human Serum ◽

Conformational Change ◽

Intrinsic Fluorescence ◽

Serum Transferrin ◽

Iron Release ◽

Human Serum Transferrin

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Mutagenesis of the aspartic acid ligands in human serum transferrin: lobe–lobe interaction and conformation as revealed by antibody, receptor-binding and iron-release studies

Biochemical Journal ◽

10.1042/bj3300035 ◽

1998 ◽

Vol 330 (1) ◽

pp. 35-40 ◽

Cited By ~ 17

Author(s):

B. Anne MASON ◽

Qing-Yu HE ◽

M. Beatrice TAM ◽

T. A. Ross MacGILLIVRAY ◽

C. Robert WOODWORTH

Keyword(s):

Human Serum ◽

Aspartic Acid ◽

Culture Media ◽

Control Cell ◽

Cell System ◽

Serum Transferrin ◽

Iron Release ◽

Binding Studies ◽

Human Serum Transferrin ◽

Tissue Culture Media

Recombinant non-glycosylated human serum transferrin and mutants in which the liganding aspartic acid (D) in one or both lobes was changed to a serine residue (S) were produced in a mammalian cell system and purified from the tissue culture media. Significant downfield shifts of 20, 30, and 45 nm in the absorption maxima were found for the D63S-hTF, D392S-hTF and the double mutant, D63S/D392S-hTF when compared to wild-type hTF. A monoclonal antibody to a sequential epitope in the C-lobe of hTF reported affinity differences between the apo- and iron-forms of each mutant and the control. Cell-binding studies performed under the same buffer conditions used for the antibody work clearly showed that the mutated lobe(s) had an open cleft. It is not clear whether the receptor itself may play a role in promoting the open conformation or whether the iron remains in the cleft.

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