Relative Mobility of Human Transferrin Domains Accounts for Its Efficient Recognition and Recycling

TL;DR

This study uses molecular dynamics simulations to explore how pH influences the conformational dynamics of human transferrin, revealing mechanisms behind its efficient iron recognition, release, and recycling in different physiological environments.

Contribution

It provides detailed insights into the pH-dependent conformational changes and inter-lobe communication of human transferrin, elucidating its mechanism for iron delivery and recycling.

Findings

Residue fluctuations indicate cross talk between lobes at serum pH.

Single iron presence stabilizes C-lobe fluctuations at serum pH.

Both lobes open readily at endosomal pH, facilitating iron release.

Abstract

Human serum transferrin (hTf) transports ferric ions in the blood stream and inflamed mucosal surfaces with high affinity and delivers them to cells via receptor mediated endocytosis. A typical hTf is folded into two homologous lobes; each lobe is further divided into two similar sized domains. Three different crystal structures of hTf delineate large conformational changes involved in iron binding/dissociation. However, whether the release process follows the same trend at serum (~7.4) and endosomal (~5.6) pH remains unanswered. The specialized role of the two lobes and if communication between them leads to efficient and controlled release is also debated. Here, we study the dynamics of the full structure as well as the separate lobes in different closed, partially open, and open conformations under the nearly neutral pH conditions in the blood serum and the more acidic one in the endosome. The results corroborate experimental observations and underscore the distinguishing effect of pH on the dynamics of hTf. Furthermore, in a total of 2 {\mu}s molecular dynamics simulation of different forms of hTf, residue fluctuations elucidate the cross talk between the two lobes correlated by the peptide linker bridging the two lobes at serum pH, while their correlated motions is lost under endosomal conditions. At serum pH, the presence of even a single iron on either lobe leads C-lobe fluctuations to subside, making it the target for recognition by human cells or hostile bacteria seeking iron sequestration. The N-lobe, on the other hand, has a propensity to open, making iron readily available when needed at regions of serum pH. At endosomal pH, both lobes readily open, making irons available for delivery. The interplay between the relative mobility of the lobes renders efficient mechanism for the recognition and release of hTf at the cell surface, and therefore its recycling in the organism.