Transferrin
  • used for Fe transport in vertebrates (some arthropods, molluscs)
  • different types found in different fluids: serum Tf (blood), ovoTf (egg whites), lactoferrin (milk, saliva)
  • ~80kDa, one chain, two lobes, each lobe has two domains
  • each lobe binds one Fe(III), octahedral 2 x OTyr NHis OAsp + exogenous bidentate [CO3]2–


Rabbit serum transferrin

Only serum Tfs bind Fe reversibly under physiological conditions, used to deliver Fe to rapidly-growing cells
• serum Tf binds to cell receptor, endocytosed
• within cell, pH drops, triggering loss of Fe at pH ~5.5
• Fe uptake/release involves structural change

How does pH control this?
• normally, lysine pKa ~10
• dilysine bridge pKa ~7
• protonate bridge, two (+) charges repel the lobes
• mutation of either Lys residue retards Fe loss by ~100x

hTf/2N, pH 7.7
 ApohTf/2N pH 5.3

Protonation also weakens Fe binding
• [CO3]2– held in place/shielded by H-bonds to Arg124
• with H+, Arg124 swings out and [HCO3]– shifts away
• loss of [HCO3]– and protonation of NHis249 accompanies loss of iron

hTf/2N, pH 7.7, conformer A
hTf/2N, pH 7.7, conformer B

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