Molecular Playground/Transferrin

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Human Se-Met transferrin complex with citrate and glycerol 2hau

One of the CBI Molecules being studied in the University of Massachusetts Amherst Chemistry-Biology Interface Program at UMass Amherst and on display at the Molecular Playground.


is a 80 KDa bilobal, iron binding glycoprotein found in blood. In Apo hTf (iron free form), N-lobe (brown) and C-lobe (green) bind one ferric ion each to regulate the concentration of free iron in blood and also transport to iron requiring cells.

N-lobe and C-lobe are homologous and contain identical iron binding amino acid residues. Structurally both N-lobe and C-lobe contain two sub domains namely NI and NII, and CI and CII which come together to form a cleft for binding iron. At the Asp63, Tyr188, Tyr95, His249 and Arg124 are involved in trapping of iron[1]. The amino acids involved in trapping of iron at the of C-lobe include Asp392, Tyr426, Tyr517, His585, Arg456[2]. In addition to these amino acids, at both the lobes a carbonate ion also plays an important role in binding iron. At low pH iron is released from N-lobe by protonation of 206 and 296 [3] and Lys534 and Arg632 in C-lobe.[4]

After binding iron N-lobe and C-lobe undergo a conformational change. In ApohTf, N lobe has an and upon binding ferric ion it shows a characterized by rotation of N-II sub domain by 63°[5]. C-lobe also undergo a similar conformational change upon binding ferric ion, however crystal structure information of the C lobe of hTf is limited due to difficulty in production[6].

Intracellular delivery of iron by transferrin is carried out by clathrin-dependent receptor-mediated endocytosis. At pH 7.4 diferric human transferrin binds to human transferrin receptor (hTfR). Upon binding, diferric hTf-hTfR is internalized and in the acidic condition of endosome iron is release from diferric hTf-hTfR complex into the cells. Apo hTf-hTfR complex is recycled back to the cell surface and at pH of cell surface Tf dissociates from the TfR to bind iron again.[7][8].



Molecular Playground banner: A bilobal protein that binds iron and transport it inside the cell.

3D structures of transferrin

Transferrin

References

  1. MacGillivray RT, Moore SA, Chen J, Anderson BF, Baker H, Luo Y, Bewley M, Smith CA, Murphy ME, Wang Y, Mason AB, Woodworth RC, Brayer GD, Baker EN. Two high-resolution crystal structures of the recombinant N-lobe of human transferrin reveal a structural change implicated in iron release. Biochemistry. 1998 Jun 2;37(22):7919-28. PMID:9609685 doi:10.1021/bi980355j
  2. Mason AB, Halbrooks PJ, James NG, Connolly SA, Larouche JR, Smith VC, MacGillivray RT, Chasteen ND. Mutational analysis of C-lobe ligands of human serum transferrin: insights into the mechanism of iron release. Biochemistry. 2005 Jun 7;44(22):8013-21. PMID:15924420 doi:10.1021/bi050015f
  3. MacGillivray RT, Moore SA, Chen J, Anderson BF, Baker H, Luo Y, Bewley M, Smith CA, Murphy ME, Wang Y, Mason AB, Woodworth RC, Brayer GD, Baker EN. Two high-resolution crystal structures of the recombinant N-lobe of human transferrin reveal a structural change implicated in iron release. Biochemistry. 1998 Jun 2;37(22):7919-28. PMID:9609685 doi:10.1021/bi980355j
  4. Byrne SL, Chasteen ND, Steere AN, Mason AB. The unique kinetics of iron release from transferrin: the role of receptor, lobe-lobe interactions, and salt at endosomal pH. J Mol Biol. 2010 Feb 12;396(1):130-40. doi: 10.1016/j.jmb.2009.11.023. Epub 2009 , Nov 13. PMID:19917294 doi:10.1016/j.jmb.2009.11.023
  5. Jeffrey PD, Bewley MC, MacGillivray RT, Mason AB, Woodworth RC, Baker EN. Ligand-induced conformational change in transferrins: crystal structure of the open form of the N-terminal half-molecule of human transferrin. Biochemistry. 1998 Oct 6;37(40):13978-86. PMID:9760232 doi:10.1021/bi9812064
  6. Mason AB, Tam BM, Woodworth RC, Oliver RW, Green BN, Lin LN, Brandts JF, Savage KJ, Lineback JA, MacGillivray RT. Receptor recognition sites reside in both lobes of human serum transferrin. Biochem J. 1997 Aug 15;326 ( Pt 1):77-85. PMID:9337853
  7. Giannetti AM, Halbrooks PJ, Mason AB, Vogt TM, Enns CA, Bjorkman PJ. The molecular mechanism for receptor-stimulated iron release from the plasma iron transport protein transferrin. Structure. 2005 Nov;13(11):1613-23. PMID:16271884 doi:10.1016/j.str.2005.07.016
  8. Klausner RD, Ashwell G, van Renswoude J, Harford JB, Bridges KR. Binding of apotransferrin to K562 cells: explanation of the transferrin cycle. Proc Natl Acad Sci U S A. 1983 Apr;80(8):2263-6. PMID:6300904

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