Single Particle Cryo-EM structure of the complex between human Ferritin and Transferrin Receptor: a gateway for targeted delivery and theranostics
The human transferrin receptor 1 (TfR1) is a heavy duty carrier capable of recognizing and internalizing iron-loaded transferrin and ferritin in order to guarantee adequate cellular iron supply, providing the main contribution to the regulation of intracellular iron homeostasis. The receptor is also opportunistically exploited by several viruses and malaria parasites as a preferential entry for cell invasion. The structural features of TfR1 interaction with transferrin and viruses have been recently clarified and specific transferrin and viruses recognition epitopes have been identified. Conversely, information on the structural elements that guide the TfR1-ferritin recognition was missing and we obtained by single-particle cryo-electron microscopy the CD71/H-ferritin complex at 3.9 Å resolution, revealing the structural basis of this interaction. We observed that two short motifs upon the H-ferritin homopolymer recognize a precise epitope on CD71 that overlaps the arenaviruses and Plasmodium vivax binding region in the apical part of the receptor ectodomain. Our structural data account for transferrin independent binding of ferritin to CD71 and suggest that viruses and parasites have adapted to enter cells by mimicking ferritin access gate. The use of single-particle cryo-electron microscopy in designing nanoparticles for targeted delivery and theranostics will be discussed highlighting its potential in the field of nanomedicine.