Search keywords: 'transferrin family' Search Date 2/15/07

Some review abstracts of interest:

• Curr Med Chem. 2005;12(23):2683-93. Structure/function overview of proteins involved in iron storage and transport.

Sargent PJ, Farnaud S, Evans RW.

Metalloprotein Research Group, Randall Research Division of Cell and Molecular Biophysics, King's College London, New Hunt's House, Guy's Campus, London SE1 1UL, UK.

Iron, the major trace element in the body, is an essential component of many proteins and enzymes. As low-molecular-weight iron is potentially toxic to cells, higher organisms express a number of proteins for the transport and storage of iron. We review our current understanding of the intestinal absorption of iron in the light of recently identified membrane proteins, namely the ferrric reductase, Dcytb, the two iron(II) transport proteins, DMT1 and ferroportin/Ireg1, and hephaestin, the membrane-bound homologue of the ferroxidase ceruloplasmin. Two types of mammalian transferrin receptor, TfR1? and TfR2? , are now known to exist. The structure of TfR1? and its role in the process of receptor-mediated cellular uptake of iron are presented together with structural information on the iron storage protein ferritin. Mechanisms for the regulation of levels of TfR1? and ferritin, as well as other proteins involved in iron homeostasis, are discussed. Our current knowledge and understanding of the structure of members of the transferrin family of iron-binding proteins and the nature of the iron-binding centres in transferrins is presented, together with information on the processes of iron-uptake and iron-release by transferrin and a summary of the elements that have been found to bind to transferrins.

PMID: 16305465 [PubMed - indexed for MEDLINE]

• Comp Biochem Physiol B Biochem Mol Biol. 2005 Oct;142(2):129-41. Evolution of the transferrin family: conservation of residues associated with iron and anion binding.

Lambert LA, Perri H, Halbrooks PJ, Mason AB.

Department of Biology, Chatham College, Woodland Road, Pittsburgh, PA 15232, USA.

The transferrin family spans both vertebrates and invertebrates. It includes serum transferrin, ovotransferrin, lactoferrin, melanotransferrin, inhibitor of carbonic anhydrase, saxiphilin, the major yolk protein in sea urchins, the crayfish protein, pacifastin, and a protein from green algae. Most (but not all) contain two domains of around 340 residues, thought to have evolved from an ancient duplication event. For serum transferrin, ovotransferrin and lactoferrin each of the duplicated lobes binds one atom of Fe (III) and one carbonate anion. With a few notable exceptions each iron atom is coordinated to four conserved amino acid residues: an aspartic acid, two tyrosines, and a histidine, while anion binding is associated with an arginine and a threonine in close proximity. These six residues in each lobe were examined for their evolutionary conservation in the homologous N- and C-lobes of 82 complete transferrin sequences from 61 different species. Of the ligands in the N-lobe, the histidine ligand shows the most variability in sequence. Also, of note, four of the twelve insect transferrins have glutamic acid substituted for aspartic acid in the N-lobe (as seen in the bacterial ferric binding proteins). In addition, there is a wide spread substitution of lysine for the anion binding arginine in the N-lobe in many organisms including all of the fish, the sea squirt and many of the unusual family members i.e., saxiphilin and the green alga protein. It is hoped that this short analysis will provide the impetus to establish the true function of some of the TF family members that clearly lack the ability to bind iron in one or both lobes and additionally clarify the evolutionary history of this important family of proteins.

PMID: 16111909 [PubMed - indexed for MEDLINE]

• Crit Rev Clin Lab Sci. 2003 Apr;40(2):151-82. Molecular mechanisms and regulation of iron transport.

Chung J, Wessling-Resnick M.

Department of Nutrition, Harvard School of Public Health, 665 Huntington Avenue, Boston, MA 02115, USA.

Iron homeostasis is primarily maintained through regulation of its transport. This review summarizes recent discoveries in the field of iron transport that have shed light on the molecular mechanisms of dietary iron uptake, pathways for iron efflux to and between peripheral tissues, proteins implicated in organellar transport of iron (particularly the mitochondrion), and novel regulators that have been proposed to control iron assimilation. The transport of both transferrin-bound and nontransferrin-bound iron to peripheral tissues is discussed. Finally, the regulation of iron transport is also considered at the molecular level, with posttranscriptional, transcriptional, and posttranslational control mechanisms being reviewed.

PMID: 12755454 [PubMed - indexed for MEDLINE]

• Am J Med Sci. 1999 Oct;318(4):213-29. Iron absorption and transport.

Conrad ME, Umbreit JN, Moore EG.

USA Cancer Center, University of South Alabama, Mobile 36688, USA. mconrad@usamail.usouthal.edu

Iron is vital for living organisms because it is essential for multiple metabolic processes to include oxygen transport, DNA synthesis, and electron transport. However, iron must be bound to proteins to prevent tissue damage from free radical formation. Thus, its concentrations in body organs must be regulated carefully. Intestinal absorption is the primary mechanism regulating iron concentrations in the body. Three pathways for intestinal iron uptake have been proposed and reported. These are the mobilferrin-integrin pathway, the divalent cation transporter 1 (DCT-1) [or natural resistance-associated macrophage protein (Nramp2)] pathway, and a separate pathway for uptake of heme by absorptive cells. Each of these pathways are incompletely described. However, studies with blocking antibodies, observations in rodents with disorders of iron metabolism, and studies in tissue culture cells suggest that the DCT-1 pathway is dominant in embryonic cells and is involved with cellular uptake of ferrous iron, whereas the mobilferrin-integrin pathway facilitates absorption of dietary inorganic ferric iron. Thus, there are separate pathways for cellular uptake of ferric and ferrous inorganic iron. Body iron can enter intestinal cells from plasma via basolateral membranes containing the classical transferrin receptor pathway with a high affinity for holotransferrin. This keeps the absorptive cell informed of the state of iron repletion of the host. Intestinal mucosal cell iron seems to exit the cell via a distinct apotransferrin receptor and a newly described protein named hephaestin. Unlike the absorptive surface of intestinal cells, most other cells possess transferrin receptors on their surfaces and the vast majority of iron entering these cells is transferrin associated. There seem to be 2 distinct pathways by which transferrin iron enters nonintestinal cells. In the classical clathrin-coated pitendosome pathway, iron accompanies transferrin into the cell to enter a vesicle, which releases the iron to the cytosol with acidification (high affinity, low capacity). Under physiological conditions, a second transferrin associated pathway (low affinity, high capacity) exists which has been named the transferrin receptor independent pathway (TRIP). How the TRIP delivers iron to cells is incompletely described. In addition, tissue culture studies show that nonintestinal cells can accept iron from soluble iron salts. This occurs via the mobilferrin-integrin and probably the DCT-1 pathways. Cellular uptake of iron from iron salts probably occurs in iron overloading disorders and may be responsible for free radical damage when the iron binding capacity of plasma is exceeded. Radioiron entering the cell via the heme and transferrin associated pathways can be found in isolates of mobilferrin/paraferritin and hemoglobin. This interaction probably occurs to permit NADPH dependent ferrireduction so iron can be used for synthesis of heme proteins. Production of heme from iron delivered via these routes indicates functional specificity for the pathways.

PMID: 10522550 [PubMed - indexed for MEDLINE] Related Links

• Comp Biochem Physiol B. 1993 Sep;106(1):203-18. Comparison of transferrin sequences from different species.

Baldwin GS.

Melbourne Tumour Biology Branch, Ludwig Institute for Cancer Research, P.O. Royal Melbourne Hospital, Victoria, Australia.

1. Amino acid sequences of transferrins from eight species, from human to tobacco hornworm, have been compared. Eighty-four amino acids (12%) are invariant, including three of the four ligands for the N-terminal Fe3+ ion. 2. The most highly conserved regions of both lobes of transferrin are the internal beta-sheets of domains 1 and 2, and helices 5 and 7 which abut the Fe3+ binding site. Two small patches of conserved surface residues, which may be involved in receptor binding, have also been identified. 3. Phylogenies have been deduced from pairwise alignment of the sequences of the N- and C-terminal lobes independently. The phylogenies are consistent with the evolutionary tree derived from the fossil record, and with the observation that the gene duplication which created the N- and C-terminal lobes of transferrin occurred before the divergence of the mammalian and insect lines. 4. The phylogenies predict that the lactotransferrin family diverged some 200 Myr ago, after the separation of the lines leading to mammals and birds. In contrast, the phylogenies predict that melanotransferrin diverged before the separation of the mammalian and avian lines. 5. Sequence comparisons also suggest that the stoichiometry of the transferrin receptor:transferrin complex is 2:1.

PMID: 8403849 [PubMed - indexed for MEDLINE]

• Adv Genet. 1988;25:1-38. Transferrin: evolution and genetic regulation of expression.

Bowman BH, Yang FM, Adrian GS.

Department of Cellular and Structural Biology, University of Texas Health Science Center, San Antonio 78284.

PMID: 3057819 [PubMed - indexed for MEDLINE]

-- DaniPershouse - 15 Feb 2007