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Ligand variation in the transferrin family: the crystal structure of the H249Q mutant of the human transferrin N-lobe as a model for iron binding in insect transferrins.

Baker HM, Mason AB, He QY, MacGillivray RT, Baker EN
Biochemistry 40 11670-5 (2001)
Cited: 12 times
EuropePMC logo PMID: 11570867

Abstract

Proteins of the transferrin (Tf) family play a central role in iron homeostasis in vertebrates. In vertebrate Tfs, the four iron-binding ligands, 1 Asp, 2 Tyr, and 1 His, are invariant in both lobes of these bilobal proteins. In contrast, there are striking variations in the Tfs that have been characterized from insect species; in three of them, sequence changes in the C-lobe binding site render it nonfunctional, and in all of them the His ligand in the N-lobe site is changed to Gln. Surprisingly, mutagenesis of the histidine ligand, His249, to glutamine in the N-lobe half-molecule of human Tf (hTf/2N) shows that iron binding is destabilized and suggests that Gln249 does not bind to iron. We have determined the crystal structure of the H249Q mutant of hTf/2N and refined it at 1.85 A resolution (R = 0.221, R(free) = 0.246). The structure reveals that Gln249 does coordinate to iron, albeit with a lengthened Fe-Oepsilon1 bond of 2.34 A. In every other respect, the protein structure is unchanged from wild-type. Examination of insect Tf sequences shows that the K206.K296 dilysine pair, which aids iron release from the N-lobes of vertebrate Tfs, is not present in the insect proteins. We conclude that substitution of Gln for His does destabilize iron binding, but in the insect Tfs this is compensated by the loss of the dilysine interaction. The combination of a His ligand with the dilysine pair in vertebrate Tfs may have been a later evolutionary development that gives more sophisticated pH-mediated control of iron release from the N-lobe of transferrins.

Articles - 1jqf mentioned but not cited (1)

  1. Structural insights into the extracytoplasmic thiamine-binding lipoprotein p37 of Mycoplasma hyorhinis. Sippel KH, Robbins AH, Reutzel R, Boehlein SK, Namiki K, Goodison S, Agbandje-McKenna M, Rosser CJ, McKenna R. J Bacteriol 191 2585-2592 (2009)


Reviews citing this publication (2)

  1. Dealing with iron: common structural principles in proteins that transport iron and heme. Baker HM, Anderson BF, Baker EN. Proc Natl Acad Sci U S A 100 3579-3583 (2003)
  2. Lactoferrin: from the structure to the functional orchestration of iron homeostasis. Ianiro G, Rosa L, Bonaccorsi di Patti MC, Valenti P, Musci G, Cutone A. Biometals 36 391-416 (2023)

Articles citing this publication (9)

  1. The major yolk protein in sea urchins is a transferrin-like, iron binding protein. Brooks JM, Wessel GM. Dev Biol 245 1-12 (2002)
  2. Crystal structure of Pasteurella haemolytica ferric ion-binding protein A reveals a novel class of bacterial iron-binding proteins. Shouldice SR, Dougan DR, Williams PA, Skene RJ, Snell G, Scheibe D, Kirby S, Hosfield DJ, McRee DE, Schryvers AB, Tari LW. J Biol Chem 278 41093-41098 (2003)
  3. Differential regulation of transferrin 1 and 2 in Aedes aegypti. Zhou G, Velasquez LS, Geiser DL, Mayo JJ, Winzerling JJ. Insect Biochem Mol Biol 39 234-244 (2009)
  4. The induction of nitric oxide response of carp macrophages by transferrin is influenced by the allelic diversity of the molecule. Jurecka P, Irnazarow I, Stafford JL, Ruszczyk A, Taverne N, Belosevic M, Belosevic M, Savelkoul HF, Wiegertjes GF. Fish Shellfish Immunol 26 632-638 (2009)
  5. Transferrin-derived synthetic peptide induces highly conserved pro-inflammatory responses of macrophages. Haddad G, Belosevic M, Belosevic M. Mol Immunol 46 576-586 (2009)
  6. Reptilian transferrins: evolution of disulphide bridges and conservation of iron-binding center. Ciuraszkiewicz J, Biczycki M, Maluta A, Martin S, Watorek W, Olczak M. Gene 396 28-38 (2007)
  7. Neutralizing antibodies induced in immunized macaques recognize the CD4-binding site on an occluded-open HIV-1 envelope trimer. Yang Z, Dam KA, Bridges MD, Hoffmann MAG, DeLaitsch AT, Gristick HB, Escolano A, Gautam R, Martin MA, Nussenzweig MC, Hubbell WL, Bjorkman PJ. Nat Commun 13 732 (2022)
  8. Incorporation of transuranium elements: coordination of Cm(iii) to human serum transferrin. Adam N, Trumm M, Smith VC, MacGillivray RTA, Panak PJ. Dalton Trans 47 14612-14620 (2018)
  9. Course of Plasmodium infection studied using 2D-COS on human erythrocytes. Birczyńska-Zych M, Czepiel J, Łabanowska M, Kucharska M, Kurdziel M, Biesiada G, Garlicki A, Wesełucha-Birczyńska A. Malar J 22 188 (2023)


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