期刊
METALLOMICS
卷 13, 期 12, 页码 -出版社
OXFORD UNIV PRESS
DOI: 10.1093/mtomcs/mfab065
关键词
ceruloplasmin; transferrin; iron; zinc; zinc-bound ceruloplasmin; ceruloplasmin-transferrin interaction
资金
- Japan Society for the Promotion of Science [18K11133]
- Grants-in-Aid for Scientific Research [18K11133] Funding Source: KAKEN
The study investigates the interaction mechanism between ceruloplasmin and transferrin mediated by zinc. The findings suggest that zinc may play a role in the transfer of iron between ceruloplasmin and transferrin.
Fe(II) exported from cells is oxidized to Fe(III), possibly by a multicopper ferroxidase (MCF) such as ceruloplasmin (CP), to efficiently bind with the plasma iron transport protein transferrin (TF). As unbound Fe(III) is highly insoluble and reactive, its release into the blood during the transfer from MCF to TF must be prevented. A likely mechanism for preventing the release of unbound Fe(III) is via direct interaction between MCF and TF; however, the occurrence of this phenomenon remains controversial. This study aimed to reveal the interaction between these proteins, possibly mediated by zinc. Using spectrophotometry, isothermal titration calorimetry, and surface plasmon resonance methods, we found that Zn(II)-bound CP bound to iron-free TF (apo-TF) with a K-d of 4.2 mu M and a stoichiometry CP:TF of similar to 2:1. Computational modeling of the complex between CP and apo-TF predicted that each of the three Zn(II) ions that bind to CP further binds to an acidic amino acid residue of apo-TF to play a role as a cross-linker connecting both proteins. Domain 4 of one CP molecule and domain 6 of the other CP molecule fit tightly into the clefts in the N- and C-lobes of apo-TF, respectively. Upon the binding of two Fe(III) ions to apo-TF, the resulting diferric TF [Fe(III) 2TF] dissociated from CP by conformational changes in TF. In human blood plasma, zinc deficiency reduced the production of Fe(III) 2TF and concomitantly increased the production of non-TF-bound iron. Our findings suggest that zinc may be involved in the transfer of iron between CP and TF.
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