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Human transferrin receptor 1 (CD71) guarantees iron supply by endocytosis upon binding of iron-loaded transferrin and ferritin. Arenaviruses and the malaria parasite exploit CD71 for cell invasion and epitopes on CD71 for interaction with transferrin and pathogenic hosts were identified. Here, we provide the molecular basis of the CD71 ectodomain-human ferritin interaction by determining the 3.9 Å resolution single-particle cryo-electron microscopy structure of their complex and by validating our structural findings in a cellular context. The contact surfaces between the heavy-chain ferritin and CD71 largely overlap with arenaviruses and Plasmodium vivax binding regions in the apical part of the receptor ectodomain. Our data account for transferrin-independent binding of ferritin to CD71 and suggest that select pathogens may have adapted to enter cells by mimicking the ferritin access gate. The human transferrin receptor 1 (CD71) is a transmembrane protein responsible for iron uptake. Here the authors present the 3.9 Å resolution cryo-EM structure of the CD71 ectodomain-human ferritin (H-Ft) complex and find that H-Ft binds a CD71 region different from the transferrin one that overlaps with the surface recognized by select pathogens.

The transferrin receptor (TfR) is one of the key proteins involved in cellular iron uptake. TfR-mediated endocytosis of transferrin-bound iron is the major pathway for iron acquisition by most cells in the body. Over the past three decades, the studies on TfR have made significant progress, and also, our knowledge on cell iron uptake has greatly been improved. Here we focus on recent advances in the studies on TfR and a brief discussion of the structures and functions of four different types of TfR, namely TfR1 (transferrin receptor 1), TfR2 (transferrin receptor 2), TfR3 (glyceraldehyde-3-phosphate dehydrogenase) and TfR4 (cubilin). These proteins work in different cells or organs and at different times, ensuring that cells and tissues get the iron they need. Their normal expression and function are fundamental to the body’s iron homeostasis. Exploring the role of transferrin receptors in cellular iron homeostasis Iron metabolism disorders affect many people worldwide, making it crucial to understand how the body manages iron. Here the authors review research on transferrin receptors (TfRs), which are proteins that help cells take in iron. The study focuses on four types of TfR: TfR1, TfR2, TfR3 and TfR4. TfR1 is the main receptor for iron uptake in most cells, especially red blood cells. It binds to transferrin and helps transport iron into cells. TfR2 is similar to TfR1 but plays a role in regulating hepcidin, a hormone that controls iron levels in the body. TfR3 and TfR4 are less understood but involved in rapid iron uptake during stress and in kidney function. The research highlights the importance of these receptors in maintaining iron balance. Future research could lead to new treatments for disorders caused by abnormal iron metabolism. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.

Cancer cells require high levels of iron for rapid proliferation, leading to significant upregulation of cell-surface transferrin receptor 1 (TfR1), which mediates iron uptake by binding to the iron-carrying protein transferrin 1 , 2 – 3 . Leveraging this phenomenon and the fast endocytosis rate of TfR1 (refs. 4 , 5 ), we developed transferrin receptor targeting chimeras (TransTACs), a heterobispecific antibody modality for membrane protein degradation. TransTACs are engineered to drive rapid co-internalization of a target protein of interest and TfR1 from the cell surface, and to enable target protein entry into the lysosomal degradation pathway. We show that TransTACs can efficiently degrade a diverse range of single-pass, multi-pass, native or synthetic membrane proteins, including epidermal growth factor receptor, programmed cell death 1 ligand 1, cluster of differentiation 20 and chimeric antigen receptor. In example applications, TransTACs enabled the reversible control of human primary chimeric antigen receptor T cells and the targeting of drug-resistant epidermal growth factor receptor-driven lung cancer with the exon 19 deletion/T790M/C797S mutations in a mouse xenograft model. TransTACs represent a promising new family of bifunctional antibodies for precise manipulation of membrane proteins and targeted cancer therapy. Transferrin receptor targeting chimeras have been developed that enable targeting of drug resistance in epidermal growth factor receptor-driven lung cancer and reversible control of human primary chimeric antigen receptor T cells, representing a promising new family of bifunctional antibodies for targeted cancer therapy.

Endocytosis and lysosomal trafficking of cell surface receptors can be triggered by endogenous ligands. Therapeutic approaches such as lysosome-targeting chimaeras 1 , 2 (LYTACs) and cytokine receptor-targeting chimeras 3 (KineTACs) have used this to target specific proteins for degradation by fusing modified native ligands to target binding proteins. Although powerful, these approaches can be limited by competition with native ligands and requirements for chemical modification that limit genetic encodability and can complicate manufacturing, and, more generally, there may be no native ligands that stimulate endocytosis through a given receptor. Here we describe computational design approaches for endocytosis-triggering binding proteins (EndoTags) that overcome these challenges. We present EndoTags for insulin-like growth factor 2 receptor (IGF2R) and asialoglycoprotein receptor (ASGPR), sortilin and transferrin receptors, and show that fusing these tags to soluble or transmembrane target protein binders leads to lysosomal trafficking and target degradation. As these receptors have different tissue distributions, the different EndoTags could enable targeting of degradation to different tissues. EndoTag fusion to a PD-L1 antibody considerably increases efficacy in a mouse tumour model compared to antibody alone. The modularity and genetic encodability of EndoTags enables AND gate control for higher-specificity targeted degradation, and the localized secretion of degraders from engineered cells. By promoting endocytosis, EndoTag fusion increases signalling through an engineered ligand–receptor system by nearly 100-fold. EndoTags have considerable therapeutic potential as targeted degradation inducers, signalling activators for endocytosis-dependent pathways, and cellular uptake inducers for targeted antibody–drug and antibody–RNA conjugates. Computationally designed genetically encoded proteins can be used to target surface proteins, thereby triggering endocytosis and subsequent intracellular degradation, activating signalling or increasing cellular uptake in specific tissues.

Plasmodium vivax is the most widely distributed malaria parasite that infects humans 1 . P. vivax invades reticulocytes exclusively, and successful entry depends on specific interactions between the P. vivax reticulocyte-binding protein 2b ( Pv RBP2b) and transferrin receptor 1 (TfR1) 2 . TfR1-deficient erythroid cells are refractory to invasion by P. vivax , and anti- Pv RBP2b monoclonal antibodies inhibit reticulocyte binding and block P. vivax invasion in field isolates 2 . Here we report a high-resolution cryo-electron microscopy structure of a ternary complex of Pv RBP2b bound to human TfR1 and transferrin, at 3.7 Å resolution. Mutational analyses show that Pv RBP2b residues involved in complex formation are conserved; this suggests that antigens could be designed that act across P. vivax strains. Functional analyses of TfR1 highlight how P. vivax hijacks TfR1, an essential housekeeping protein, by binding to sites that govern host specificity, without affecting its cellular function of transporting iron. Crystal and solution structures of Pv RBP2b in complex with antibody fragments characterize the inhibitory epitopes. Our results establish a structural framework for understanding how P. vivax reticulocyte-binding protein engages its receptor and the molecular mechanism of inhibitory monoclonal antibodies, providing important information for the design of novel vaccine candidates. Structural studies show that conserved residues in Plasmodium vivax reticulocyte-binding protein 2b determine interactions with transferrin receptor 1 that are essential for host invasion, suggesting avenues for designing vaccines that work across P. vivax strains.

Disrupted brain iron homeostasis is a common feature of neurodegenerative disease. To begin to understand how neuronal iron handling might be involved, we focused on dopaminergic neurons and asked how inactivation of transport proteins affected iron homeostasis in vivo in mice. Loss of the cellular iron exporter, ferroportin, had no apparent consequences. However, loss of transferrin receptor 1, involved in iron uptake, caused neuronal iron deficiency, age-progressive degeneration of a subset of dopaminergic neurons, and motor deficits. There was gradual depletion of dopaminergic projections in the striatum followed by death of dopaminergic neurons in the substantia nigra. Damaged mitochondria accumulated, and gene expression signatures indicated attempted axonal regeneration, a metabolic switch to glycolysis, oxidative stress, and the unfolded protein response. We demonstrate that loss of transferrin receptor 1, but not loss of ferroportin, can cause neurodegeneration in a subset of dopaminergic neurons in mice.

The safe and efficient delivery of chemotherapeutic agents is critical to glioma therapy. However, chemotherapy for glioma is extremely challenging because the blood-brain barrier (BBB) rigorously prevents drugs from reaching the tumor region. TfR-T12 peptide-modified PEG-PLA polymer was synthesized to deliver paclitaxel (PTX) for glioma therapy. TfR was significantly expressed on brain capillary endothelial cells and glioma cells; therefore, TfR-T12 peptide-modified micelles can cross the BBB system and target glioma cells. TfR-T12-PEG-PLA/PTX polymeric micelles (TfR-T12-PMs) could be absorbed rapidly by tumor cells, and traversed effectively the BBB monolayers. TfR-T12-PMs can effectively inhibit the proliferation of U87MG cells in vitro, and TfR-T12-PMs loaded with paclitaxel presented better antiglioma effect with prolonged median survival of nude mice-bearing glioma than the unmodified PMs. The TfR-T12-PMs could effectively overcome the BBB barrier and accomplish glioma-targeted drug delivery, thus validating its potential in improving the therapeutic outcome in multiforme.

Raif Geha, Louis Kunkel, Waleed Al-Herz and colleagues report a mutation in TFRC (encoding transferrin receptor 1, TfR1) that causes combined immunodeficiency characterized by impaired function of T and B cells in homozygous patients. Iron citrate rescued the lymphocyte defects in patient-derived cells and in a mouse model, demonstrating the importance of TfR1-mediated iron internalization in adaptive immunity. Patients with a combined immunodeficiency characterized by normal numbers but impaired function of T and B cells had a homozygous p.Tyr20His substitution in transferrin receptor 1 (TfR1), encoded by TFRC . The substitution disrupts the TfR1 internalization motif, resulting in defective receptor endocytosis and markedly increased TfR1 expression on the cell surface. Iron citrate rescued the lymphocyte defects, and expression of wild-type but not mutant TfR1 rescued impaired transferrin uptake in patient-derived fibroblasts. Tfrc Y20H/Y20H mice recapitulated the immunological defects of patients. Despite the critical role of TfR1 in erythrocyte development and function, patients had only mild anemia and only slightly increased TfR1 expression in erythroid precursors. We show that STEAP3, a metalloreductase expressed in erythroblasts, associates with TfR1 and partially rescues transferrin uptake in patient-derived fibroblasts, suggesting that STEAP3 may provide an accessory TfR1 endocytosis signal that spares patients from severe anemia. These findings demonstrate the importance of TfR1 in adaptive immunity.

The de novo design of polar protein–protein interactions is challenging because of the thermodynamic cost of stripping water away from the polar groups. Here, we describe a general approach for designing proteins which complement exposed polar backbone groups at the edge of beta sheets with geometrically matched beta strands. We used this approach to computationally design small proteins that bind to an exposed beta sheet on the human transferrin receptor (hTfR), which shuttles interacting proteins across the blood–brain barrier (BBB), opening up avenues for drug delivery into the brain. We describe a design which binds hTfR with a 20 nM K d, is hyperstable, and crosses an in vitro microfluidic organ-on-a-chip model of the human BBB. Our design approach provides a general strategy for creating binders to protein targets with exposed surface beta edge strands.

Metastasis Associated in Colon Cancer 1 (MACC1) is a novel prognostic, predictive and causal biomarker for tumor progression and metastasis in many cancer types, including colorectal cancer. Besides its clinical value, little is known about its molecular function. Its similarity to SH3BP4, involved in regulating uptake and recycling of transmembrane receptors, suggests a role of MACC1 in endocytosis. By exploring the MACC1 interactome, we identified the clathrin-mediated endocytosis (CME)-associated proteins CLTC, DNM2 and AP-2 as MACC1 binding partners. We unveiled a MACC1-dependent routing of internalized transferrin receptor towards recycling. Elevated MACC1 expression caused also the activation and internalization of EGFR, a higher rate of receptor recycling, as well as earlier and stronger receptor activation and downstream signaling. These effects are limited by deletion of CME-related protein interaction sites in MACC1. Thus, MACC1 regulates CME and receptor recycling, causing increased growth factor-mediated downstream signaling and cell proliferation. This novel mechanism unveils potential therapeutic intervention points restricting MACC1-driven metastasis.