X-ray solution scattering reveals conformational changes upon iron uptake in lactoferrin, serum and ovo-transferrins

Jg, Grossmann; Neu, M.; Pantos, E.; Fj, Schwab; Rw, Evans; E, Townes-Andrews; Pf, Lindley; Appel, H.; Wg, Thies; Ss, Hasnain

doi:10.1016/0022-2836(92)90402-6

Cited by 141 publications

(97 citation statements)

References 17 publications

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“…This was not sufficient information to determine the correct solution. The similar large changes in the orientation of the N2 and C2 domains of 51.6 and 49.9 °, respectively (Table 2) confirm the conclusions of the X-ray solution scattering (Grossmann et al, 1992). This indicated that both the N and the C lobes are open in the apo structure and that the opening of the C lobe is equivalent to 75% of the opening of the N lobe but did not rule out a wider opening of the C lobe in solution similar to that observed for the N lobe in the crystal structure of APOHLT.…”

Section: Data Collectionsupporting

confidence: 78%

“…Since X-ray scattering studies in solution (Grossmann et al, 1992) suggested that both lobes should be open, while the single crystal structure of APOHLT (Norris et al, 1991) The results of these molecular replacement calculations confirmed that, for the following reasons, both the N and C lobes must be open in APODOT and that N1/C1 forms a relatively rigid core with the second domains N2 and C2 hinging on this core.…”

Section: Data Collectionmentioning

confidence: 84%

“…X-ray solution scattering studies of the intact proteins of human serum transferrin, human lactoferrin and hen ovotransferrin as well as the isolated N and C lobes of hen ovotransferrin (Grossmann et al, 1992) provided an estimation of the opening of the lobes. These studies showed that both the N and the C lobes undergo similar conformational changes when iron is bound or released.…”

Section: Introductionmentioning

confidence: 99%

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Structure of apo duck ovotransferrin: the structures of the N and C lobes are in the open form

Rawas

Muirhead²,

Williams³

1997

Acta Cryst D

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The structure of apo duck ovotransfemn (APODOT) has been determined at a resolution of 4.0A by the molecular replacement method using the structure of duck ovotransfemn (DOT) as the search model. The DOT structure contains two iron binding sites; one in the N-terminal lobe lying between domains N1 and N2 and one in the C-terminal lobe between domains C 1 and C2. Both lobes have a closed structure. Models of various forms of both the N and C lobes were used in the search. The final model was refined to give an R factor of 0.22. The comparison of the structure of APODOT with that of DOT shows that both the N and the C lobes are in an open form, where the N2 and C2 domains undergo large rigid-body rotations of 51.6 and 49.9 ° relative to the N1 and C1 domains, respectively. The interface between the N and C lobes, which is formed by the N1--C 1 contact in the core of the molecule does not change significantly. The DOT molecule may be described in terms of three rigid bodies; the N1 and C1 domains as one rigid body forming the static core of the molecule and the N2 and C2 domains as two other rigid bodies which, on the release of iron, move away from the static core of the molecule to form the open structure of APODOT.

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Section: Data Collectionsupporting

confidence: 78%

Section: Data Collectionmentioning

confidence: 84%

Section: Introductionmentioning

confidence: 99%

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Structure of apo duck ovotransferrin: the structures of the N and C lobes are in the open form

Rawas

Muirhead²,

Williams³

1997

Acta Cryst D

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“…Besides this, the conformation of the LF protein might also be crucial, since iron-depleted hLF has no inhibitory capability. Iron binding by LF is accompanied by substantial conformational changes between the open apo form and the closed holo form (1,17). hLF and holo-hLF are partially able to block DC-mediated transmission of HIV-1, but the adhesion experiment shows no binding to DC-SIGN.…”

Section: Discussionmentioning

confidence: 99%

Lactoferrin Prevents Dendritic Cell-Mediated Human Immunodeficiency Virus Type 1 Transmission by Blocking the DC-SIGN—gp120 Interaction

Groot

Geijtenbeek²,

Sanders³

et al. 2005

J Virol

128

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One of the cell types first encountered by human immunodeficiency virus type 1 (HIV-1) following sexual transmission are dendritic cells (DC). DC capture HIV-1 through C-type lectin receptors, of which the best studied example is DC-SIGN, which mediates HIV-1 internalization. DC can keep the virus infectious for several days and are able to transmit HIV-1 to CD4؉ T cells. We tested proteins from milk and serum for their ability to block DC-mediated HIV-1 transmission, of which bovine lactoferrin (bLF) is the most potent inhibitor. bLF binds strongly to DC-SIGN, thus preventing virus capture and subsequent transmission. Interestingly, bLF is a much more efficient inhibitor of transmission than human lactoferrin. Since bLF is nontoxic and easy to purify in large quantities, it is an interesting candidate microbicide against HIV-1. Another advantage of bLF is its ability to block HIV-1 replication in T cells. DC-mediated capture of a bLF-resistant HIV-1 variant that was selected during long-term culturing in T cells could still be blocked by bLF. This underscores the usefulness of bLF as a microbicide drug to prevent HIV-1 transmission.

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“…17 When fully iron saturated (holo), LF presents as a stable closed structure, as opposed to its open iron-free state (apo). 18,19 Furthermore, the structure of this protein, although differs throughout species, 16,20 retains essentially identical high-affinity (K D *10 -22 M) iron-binding sites. 21 The role of iron concentration and the resulting changes in protein conformation in modulating the bioactivity of LF is not clearly understood.…”

Section: Introductionmentioning

confidence: 98%

Evaluation of the Bioactivity of Recombinant Human Lactoferrins Toward Murine Osteoblast-Like Cells for Bone Tissue Engineering

Amini

Nair

2013

Tissue Engineering Part A

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Lactoferrin (LF), which belongs to the iron-binding transferrin family, is an important regulator of the levels of free iron in the body fluids. LF has raised significant interest as a bioactive protein due to its wide array of physiological effects on many different cell types, including osteoblasts and osteoclasts. The glycoprotein's degree of iron saturation has a pivotal influence on its physical structure. The objective of this study is to investigate the biological effects of apo (low iron saturation), pis (partially iron saturated), and holo (high iron saturation) recombinant human LF (rhLF) on MC3T3-E1 cells to identify the suitable candidate for bone tissue engineering application. Our studies demonstrated a dose-dependent mitogenic response of MC3T3 to rhLF treatment irrespective of the iron concentration. Furthermore, rhLF induced the cells to produce transcription factors, chemokines, and cytokines as determined by b-catenin activation, phosphorylation of Akt, vascular endothelial growth factor, and interleukin (IL-6) expression. The iron saturation of rhLF did not have any significant effect on these biological activities of MC3T3 cells. In addition, the overall pattern of gene regulation in MC3T3-E1 cells upon rhLF treatment was followed by a global microarray analysis. Among the 45,200 genes tested, only 251 genes were found to be regulated by rhLFs of different iron concentrations. Of these, the transferrin receptor (Tfrc) was the only gene differentially regulated by the iron saturated and iron depleted (apo) rhLFs. In conclusion, the study demonstrated that rhLF is a bioactive protein and that the iron saturation of rhLF may not play a significant role in modulating osteoblast functions.

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X-ray solution scattering reveals conformational changes upon iron uptake in lactoferrin, serum and ovo-transferrins

Cited by 141 publications

References 17 publications

Structure of apo duck ovotransferrin: the structures of the N and C lobes are in the open form

Structure of apo duck ovotransferrin: the structures of the N and C lobes are in the open form

Lactoferrin Prevents Dendritic Cell-Mediated Human Immunodeficiency Virus Type 1 Transmission by Blocking the DC-SIGN—gp120 Interaction

Evaluation of the Bioactivity of Recombinant Human Lactoferrins Toward Murine Osteoblast-Like Cells for Bone Tissue Engineering

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