Transferrin

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Dietmar Steverding - One of the best experts on this subject based on the ideXlab platform.

  • The significance of Transferrin receptor variation in Trypanosoma brucei.
    Trends in parasitology, 2003
    Co-Authors: Dietmar Steverding
    Abstract:

    The Transferrin receptor of Trypanosoma brucei is encoded by genes located in different expression sites. The various expression sites encode slightly different Transferrin receptors, which differ substantially in their affinity for Transferrin of different host species. It was proposed that T. brucei has developed multiple expression sites encoding different Transferrin receptors not only to cope with the diversity of mammalian Transferrins, but also to ensure sufficient iron uptake in the presence of anti-Transferrin receptor antibodies. This article shows that calculations based on K(d) values argue against the first part of the hypothesis, but might support the second part.

  • Iron-dependent regulation of Transferrin receptor expression in Trypanosoma brucei.
    Biochemical Journal, 1999
    Co-Authors: Beate Fast, Katrin Kremp, Michael Boshart, Dietmar Steverding
    Abstract:

    Transferrin is an essential growth factor for African trypanosomes. Here we show that expression of the trypanosomal Transferrin receptor, which bears no structural similarity with mammalian Transferrin receptors, is regulated by iron availability. Iron depletion of bloodstream forms of Trypanosoma brucei with the iron chelator deferoxamine resulted in a 3-fold up-regulation of the Transferrin receptor and a 3-fold increase of the Transferrin uptake rate. The abundance of expression site associated gene product 6 (ESAG6) mRNA, which encodes one of the two subunits of the trypanosome Transferrin receptor, is regulated 5-fold by a post-transcriptional mechanism. In mammalian cells the stability of Transferrin receptor mRNA is controlled by iron regulatory proteins (IRPs) binding to iron-responsive elements (IREs) in the 3'-untranslated region (UTR). Therefore, the role of a T. brucei cytoplasmic aconitase (TbACO) that is highly related to mammalian IRP-1 was investigated. Iron regulation of the Transferrin receptor was found to be unaffected in Deltaaco::NEO/Deltaaco::HYG null mutants generated by targeted disruption of the TbACO gene. Thus, the mechanism of post-transcriptional Transferrin receptor regulation in trypanosomes appears to be distinct from the IRE/IRP paradigm. The Transferrin uptake rate was also increased when trypanosomes were transferred from medium supplemented with foetal bovine serum to medium supplemented with sera from other vertebrates. Due to varying binding affinities of the trypanosomal Transferrin receptor for Transferrins of different species, serum change can result in iron starvation. Thus, regulation of Transferrin receptor expression may be a fast compensatory mechanism upon transmission of the parasite to a new host species.

Ann M. Valentine - One of the best experts on this subject based on the ideXlab platform.

  • Isolation and characterization of the iron-binding properties of a primitive monolobal Transferrin from Ciona intestinalis
    JBIC Journal of Biological Inorganic Chemistry, 2008
    Co-Authors: Ritika Uppal, K. V. Lakshmi, Ann M. Valentine
    Abstract:

    Transferrins are bilobal glycoproteins responsible for iron binding, transport, and delivery in many higher organisms. The two homologous lobes of Transferrins are thought to have evolved by gene duplication of an ancestral monolobal form. In the present study, a 37.7-kDa primitive monolobal Transferrin (nicaTransferrin, or nicaTf) from the serum of the model ascidian species Ciona intestinalis was isolated by using an immobilized iron-affinity column and characterized by using mass spectrometry and N-terminal sequencing. The protein binds one equivalent of iron(III) and exhibits an electron paramagnetic resonance spectrum that is anion-dependent. The UV/vis spectrum of nicaTf has a shoulder at 330 nm in both the iron-depleted and the iron-replete forms, but does not display the approximately 460 nm tyrosine-to-iron charge transfer band common to vertebrate serum Transferrins under the conditions investigated. This result suggests that iron may adopt a different binding mode in nicaTf compared with the more highly evolved Transferrin proteins. This difference in binding mode could have implications for the physiological role of the protein in the ascidian. The genome of C. intestinalis has genes for both a monolobal and a bilobal Transferrin, and the sequences of both proteins are discussed in light of the known features of vertebrate serum Transferrins as well as other Transferrin homologs.

  • on the evolutionary significance and metal binding characteristics of a monolobal Transferrin from ciona intestinalis
    Proceedings of the National Academy of Sciences of the United States of America, 2008
    Co-Authors: Arthur D Tinoco, Cynthia W Peterson, Baldo Lucchese, Robert P Doyle, Ann M. Valentine
    Abstract:

    Transferrins are a family of proteins that bind and transport Fe(III). Modern Transferrins are typically bilobal and are believed to have evolved from an ancient gene duplication of a monolobal form. A novel monolobal Transferrin, nicaTransferrin (nicaTf), was identified in the primitive ascidian species Ciona intestinalis that possesses the characteristic features of the proposed ancestral Tf protein. In this work, nicaTf was expressed in Pichia pastoris. Extensive solution studies were performed on nicaTf, including UV-vis, fluorescence, CD, EPR and NMR spectroscopies, and electrospray time-of-flight mass spectrometry. The expressed protein is nonglycosylated, unlike the protein isolated from the organism. This property does not affect its ability to bind Fe(III). However, Fe(III)-bound nicaTf displays important spectral differences from other Fe(III)-bound Transferrins, which are likely the consequence of differences in metal coordination. Coordination differences could also account for the weaker affinity of nicaTf for Fe(III) (log K = 18.5) compared with bilobal human serum Transferrin (HsTf) (log K = 22.5 and 21.4). The Fe–nicaTf complex is not labile, as indicated by slow metal removal kinetics by the high-affinity chelator tiron at pH 7.4. The protein alternatively binds up to one equivalent of Ti(IV) or V(V), which suggests that it may transport nonferric metals. These solution studies provide insight into the structure and function of the primitive monolobal Transferrin of C. intestinalis for comparison with higher order bilobal Transferrins. They suggest that a major advantage for the evolution of modern Transferrins, dominantly of bilobal form, is stronger Fe(III) affinity because of cooperativity.

Trevor F Moraes - One of the best experts on this subject based on the ideXlab platform.

  • Transferrin binding protein b and Transferrin binding protein a 2 expand the Transferrin recognition range of histophilus somni
    Journal of Bacteriology, 2020
    Co-Authors: Anastassia K Pogoutse, Trevor F Moraes
    Abstract:

    The bacterial bipartite Transferrin receptor is an iron acquisition system that several important human and animal pathogens require for survival. It consists of the TonB-dependent transporter Transferrin binding protein A (TbpA) and the surface lipoprotein Transferrin binding protein B (TbpB). Curiously, the Tbps are only found in host-specific pathogens, and are themselves host-specific, meaning that they will bind to the Transferrin of their host species, but not to the Transferrins of other animal species. While this phenomenon has long been established, neither the steps in the evolutionary process that led to this exquisite adaptation for the host, nor the steps that could alter it, are known. We sought to gain insight into these processes by studying Tbp specificity in Histophilus somni, an economically important pathogen of cattle. A past study showed that whole cells of H. somni specifically bind bovine Transferrin, but not Transferrin from sheep and goats, two bovids whose Transferrins share 93% amino acid sequence identity with bovine Transferrin. To our surprise, we found that H. somni can use sheep and goat Transferrins as iron sources for growth, and that HsTbpB, but not HsTbpA, has detectable affinity for sheep and goat Transferrins. Furthermore, a third Transferrin binding protein found in H. somni, HsTbpA2, also showed affinity for sheep and goat Transferrins. Our results suggest that H. somni TbpB and TbpA2 may contribute to broadening the host Transferrin recognition range of H. somni. Importance Host restricted pathogens infect a single host species or a narrow range of host species. Histophilus somni, a pathogen that incurs severe economic losses for the cattle industry, infects cattle, sheep, and goats, but not other mammals. The Transferrin binding proteins, TbpA and TbpB, are thought to be a key iron acquisition system in H. somni; however, despite their importance, H. somni TbpA and TbpB were previously shown to be cattle Transferrin-specific. In our study we find that H. somni TbpB, and another little-studied Tbp, TbpA2, bind sheep and goat Transferrins as well as bovine Transferrin. Our results suggest that TbpB and TbpA2 may allow for host range expansion and provide a mechanism for how host specificity in Tbp-encoding pathogens can be altered.

  • Transferrin binding protein b and Transferrin binding protein a2 expand the Transferrin recognition range of histophilus somni
    bioRxiv, 2019
    Co-Authors: Anastassia K Pogoutse, Trevor F Moraes
    Abstract:

    Abstract The bacterial bipartite Transferrin receptor is an iron acquisition system that is required for survival by several key human and animal pathogens. It consists of the TonB-dependent transporter Transferrin binding protein A (TbpA) and the surface lipoprotein Transferrin binding protein B (TbpB). Curiously, the Tbps are only found in host specific pathogens, and are themselves host specific, meaning that they will bind to the Transferrin of their host species, but not to those of other animal species. While this phenomenon has long been established, neither the steps in the evolutionary process that led to this exquisite adaptation for the host, nor the steps that could alter it, are known. We sought to gain insight into these processes by studying Tbp specificity in Histophilus somni, a major pathogen of cattle. A past study showed that whole cells of H. somni specifically bind bovine Transferrin, but not Transferrin from sheep and goats, two bovids whose Transferrins share 93% amino acid sequence identity with bovine Transferrin. To our surprise, we found that H. somni can use sheep and goat Transferrins as iron sources for growth, and that HsTbpB, but not HsTbpA, has detectable affinity for sheep and goat Transferrins. Furthermore, a third Transferrin binding protein, HsTbpA2, also showed affinity for sheep and goat Transferrins. Our results show that H. somni TbpB and TbpA2 act to broaden the host Transferrin recognition range of H. somni. Importance Host restricted pathogens infect a single host species or a narrow range of host species. Histophilus somni, a pathogen that incurs severe economic losses for the cattle industry, infects cattle, sheep, and goats, but not other mammals. The Transferrin binding proteins, TbpA and TbpB, are thought to be a key iron acquisition system in H. somni, however, surprisingly, they were also shown to be cattle Transferrin-specific. In our study we find that H. somni TbpB, and another little-studied Tbp, TbpA2, bind sheep and goat Transferrins as well as bovine Transferrin. Our results suggest that TbpA2 may have allowed for host range expansion, and provide a mechanism for how host specificity in Tbp containing pathogens can be altered.

Anne B Mason - One of the best experts on this subject based on the ideXlab platform.

  • indirect detection of protein metal binding interaction of serum Transferrin with in3 and bi3
    Journal of the American Society for Mass Spectrometry, 2004
    Co-Authors: Mingxuan Zhang, Dmitry R Gumerov, Igor A Kaltashov, Anne B Mason
    Abstract:

    Transferrins comprise a class of monomeric glycoproteins found in all vertebrates, whose function is iron sequestration and transport. In addition to iron, serum Transferrin also binds a variety of other metals and is believed to provide a route for the in vivo delivery of such metals to cells. In the present study, ESI MS is used to investigate interactions between human serum Transferrin and two nonferrous metals, indium (a commonly used imaging agent) and bismuth (a component of many antiulcer drugs). While the UV-Vis absorption spectroscopy measurements clearly indicate that both metals bind strongly to Transferrin in solution, the metal-protein complex can be detected by ESI MS only for indium, but not for bismuth. Despite the apparently low stability of the Transferrin-bismuth complex in the gas phase, presence of such complex in solution can be established by ESI MS indirectly. This is done by monitoring the evolution of charge state distributions of Transferrin ions upon acid-induced protein unfolding in the presence and in the absence of the metal in solution. The anomalous instability of the Transferrin-bismuth complex in the gas phase is rationalized in terms of conformational differences between this form of Transferrin and the holo-forms of this protein produced by binding of metals with smaller ionic radii (e.g., Fe3+ and In3+). The large size of Bi3+ ion is likely to prevent formation of a closed conformation (canonical structure of the holo-protein), resulting in a non-native metal coordination. It is suggested that Transferrin retains the open conformation (characteristic of the apo-form) upon binding Bi3+, with only two ligands in the metal coordination sphere provided by the protein itself. This suggestion is corroborated by the results of circular dichroism measurements in the near-UV range. Since the cellular consumption of metals in the Transferrin cycle critically depends upon recognition of the holo-protein complex by the Transferrin receptor, the noncanonical conformation of the Transferrin-bismuth complex may explain very inefficient delivery of bismuth to cells even when a high dosage of bismuth-containing drugs is administered for prolonged periods of time.

  • indirect detection of protein metal binding interaction of serum Transferrin with in3 and bi3
    Journal of the American Society for Mass Spectrometry, 2004
    Co-Authors: Mingxuan Zhang, Dmitry R Gumerov, Igor A Kaltashov, Anne B Mason
    Abstract:

    Transferrins comprise a class of monomeric glycoproteins found in all vertebrates, whose function is iron sequestration and transport. In addition to iron, serum Transferrin also binds a variety of other metals and is believed to provide a route for the in vivo delivery of such metals to cells. In the present study, ESI MS is used to investigate interactions between human serum Transferrin and two nonferrous metals, indium (a commonly used imaging agent) and bismuth (a component of many antiulcer drugs). While the UV-Vis absorption spectroscopy measurements clearly indicate that both metals bind strongly to Transferrin in solution, the metal-protein complex can be detected by ESI MS only for indium, but not for bismuth. Despite the apparently low stability of the Transferrin-bismuth complex in the gas phase, presence of such complex in solution can be established by ESI MS indirectly. This is done by monitoring the evolution of charge state distributions of Transferrin ions upon acid-induced protein unfolding in the presence and in the absence of the metal in solution. The anomalous instability of the Transferrin-bismuth complex in the gas phase is rationalized in terms of conformational differences between this form of Transferrin and the holo-forms of this protein produced by binding of metals with smaller ionic radii (e.g., Fe3+ and In3+). The large size of Bi3+ ion is likely to prevent formation of a closed conformation (canonical structure of the holo-protein), resulting in a non-native metal coordination. It is suggested that Transferrin retains the open conformation (characteristic of the apo-form) upon binding Bi3+, with only two ligands in the metal coordination sphere provided by the protein itself. This suggestion is corroborated by the results of circular dichroism measurements in the near-UV range. Since the cellular consumption of metals in the Transferrin cycle critically depends upon recognition of the holo-protein complex by the Transferrin receptor, the noncanonical conformation of the Transferrin-bismuth complex may explain very inefficient delivery of bismuth to cells even when a high dosage of bismuth-containing drugs is administered for prolonged periods of time.

Andanthony B. Schryvers - One of the best experts on this subject based on the ideXlab platform.