How the binding of human transferrin primes the transferrin receptor potentiating iron release at endosomal pH

Eckenroth, B.E.; Steere, Allen C.; Chasteen, N. Dennis; Everse, Stephen J.; Mason, Anne B.

doi:10.1073/pnas.1105786108

Cited by 136 publications

(217 citation statements)

References 41 publications

(57 reference statements)

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“…transferrin is known to interact with the protease-like domain (PD2) of TfR1 (44,45), PV capsids and transferrin would compete for this TfR1 domain, which is in agreement with the result shown in Fig. 2C.…”

Section: Journal Of Biological Chemistry 2833supporting

confidence: 81%

Transferrin Receptor 1 Facilitates Poliovirus Permeation of Mouse Brain Capillary Endothelial Cells

Mizutani

Ishizaka

Nihei

2016

Journal of Biological Chemistry

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As a possible route for invasion of the CNS, circulating poliovirus (PV) in the blood is believed to traverse the blood-brain barrier (BBB), resulting in paralytic poliomyelitis. However, the underlying mechanism is poorly understood. In this study, we demonstrated that mouse transferrin receptor 1 (mTfR1) is responsible for PV attachment to the cell surface, allowing invasion into the CNS via the BBB. PV interacts with the apical domain of mTfR1 on mouse brain capillary endothelial cells (MBEC4) in a dose-dependent manner via its capsid protein (VP1). We found that F-G, G-H, and H-I loops in VP1 are important for this binding. Poliovirus (PV)2 is an enterovirus belonging to the family Picornaviridae and is the causative agent of poliomyelitis (1, 2). Generally, PV enters the stomach via oral ingestion and invades the alimentary mucosa in an unidentified manner, and PV then proliferates in the alimentary mucosa (1, 2) and moves to the bloodstream. The circulating virus invades the CNS and replicates in motor neurons (MNs). Poliomyelitis is known to involve accumulated damage to the MNs by PV replication (3). The human PV receptor (hPVR/CD155) facilitates PV infection of cells; however, PV replication is restricted by host immune activities (e.g. IFN-␣/␤) (4 -6). Although wild-type mice are not sensitive to PV (7), hPVR-expressing transgenic (Tg) mice were susceptible to PV via intravenous and intramuscular routes but not the oral route (7-12). Further, an IFN-␣/␤-deficient hPVR-Tg mouse was found to be susceptible to PV via the oral route (13).As a possible route for invasion of the CNS, PV enters the CNS via axonal transport through the skeletal muscle in an hPVR-dependent manner (14). Endocytic vesicles at the synapse take up intact PV, which is passively transported to the CNS. Interestingly, PV has been shown to invade the CNS via hPVR-independent axonal transport in hPVR-Tg and non-Tg mice (15), indicating that other unidentified pathways for PV transport may be present. Furthermore, we previously showed that PV promptly invades the CNS from the blood in non-Tg mice, which supports this speculation (16). In that study, intravenously injected PV permeated the brain as fast as cationized rat serum albumin, which is BBB-permeable (16).Therefore, PV is thought to efficiently permeate the CNS by overcoming the BBB.The BBB is composed of a multilayer barrier composed of vascular endothelial cells with tight junctions filling the gaps between cells (17). Although the BBB was discovered over a century ago, its transport mechanisms are not fully understood. It restricts transport of substances between the CNS and blood by maintaining a strictly regulated microenvironment for high integrity neuronal response in the CNS (18,19). Certain substances are permitted transmission via the BBB from the bloodstream to the brain, facilitated by specific transporters on the cell membrane (e.g. glucose, amino acids, transferrin, and insulin) (20 -25). For example, transferrin is known to facilitate iron transport from the blood ...

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Section: Journal Of Biological Chemistry 2833supporting

confidence: 81%

Transferrin Receptor 1 Facilitates Poliovirus Permeation of Mouse Brain Capillary Endothelial Cells

Mizutani

Ishizaka

Nihei

2016

Journal of Biological Chemistry

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“…The concentration of hTF in the blood serum is 37 M[74]. In normal plasma, only 30% of transferrin is bound to Fe 3+ ions with a distribution of approximately 27% Fe 2 -hTF, 23% Fe-hTF N , 11% Fe-hTF C and 40% apo-hTF[75]; these values correspond to a concentration of ca. 50 M of available hTF binding sites.Therefore, hTF can also bind other metal ions, including Bi 3+ , Ga 3+ , In 3+ , Al 3+ , Cu 2+ , Mn 2+ , Zn 2+ , Ni 2+ , Ru 3+ , as well as vanadium in its three oxidation states (+3, +4, +5) [25][76].…”

mentioning

confidence: 99%

Vanadium and proteins: Uptake, transport, structure, activity and function

Pessoa

Garribba

Santos

et al. 2015

Coordination Chemistry Reviews

180

104

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“…This change in pH induces conformational changes within the Tf-TfR1 complex to favor the release of Fe 3 + from Tf and to stabilize the apo-Tf-TfR1 complex 2, 14 . The extent to which TfR2 undergoes a similar transition is unknown.…”

Section: Resultsmentioning

confidence: 99%

Transferrin Receptors TfR1 and TfR2 Bind Transferrin through Differing Mechanisms

2018

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Hereditary hemochromatosis (HH), a disease marked by chronic iron overload from insufficient expression of the hormone hepcidin, is one of the most common genetic diseases. One form of HH (Type III) results from mutations in the transferrin receptor-2 (TfR2). TfR2 is postulated to be a part of signaling system that is capable of modulating hepcidin expression. The molecular details of TfR2’s role in this system remain unclear, however. TfR2 is predicted to bind the iron carrier transferrin (Tf) when the iron-saturation of Tf is high. To better understand the nature of these TfR-Tf interactions, a binding study with the full-length receptors was conducted. In agreement with previous studies with truncated forms of the receptors, holo-Tf binds to the homolog, TfR1, significantly stronger than TfR2. However, the binding constant for Tf-TfR2 is still far above that of physiological holo-Tf levels, inconsistent with the hypothetical model and suggests that other factors mediate the interaction. One possible factor, Apo-Tf, only weakly binds TfR2 at serum pH, thus will not be able to effectively compete with holo-Tf. Tf-binding to a TfR2 chimera containing the TfR1-helical domain indicates that the differences in the helical domain account for differences in on-rate of Tf, and non-conserved inter-receptor interactions are necessary for the stabilization of the complex. Conserved residues at one possible site of stabilization, the apical arm junction, are not important for TfR1-Tf binding, but are critical for the TfR2-Tf interaction. Our results highlight the differences in Tf interactions with the two TfRs.

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How the binding of human transferrin primes the transferrin receptor potentiating iron release at endosomal pH

Cited by 136 publications

References 41 publications

Transferrin Receptor 1 Facilitates Poliovirus Permeation of Mouse Brain Capillary Endothelial Cells

Transferrin Receptor 1 Facilitates Poliovirus Permeation of Mouse Brain Capillary Endothelial Cells

Vanadium and proteins: Uptake, transport, structure, activity and function

Transferrin Receptors TfR1 and TfR2 Bind Transferrin through Differing Mechanisms

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