An N-terminal amphipathic helix governs activity and conformational dynamics of Nramp metal transporters
Jafari, M.; Zhao, H.; Zhang, Y.; Wang, T.; Merz, K. M.; Hu, J.
Show abstract
Nramps are a family of proton-coupled divalent metal ion transporters that play critical roles in maintaining homeostasis of essential metals. In humans, Nramp2 (DMT1) mediates iron uptake to support both cellular and systemic iron homeostasis, whereas Nramp1 exports metals from phagosomes, contributing to antimicrobial defense. A survey of experimentally solved Nramp structures reveals that an N-terminal helix (A) immediately preceding TM1 is folded only in the outward-facing or outward-facing occluded states, raising the question of its role in Nramp transport. Here, we combined mutagenesis, transport assays, and molecular dynamics simulations to investigate A. Our results show that deletion or substitution of conserved residues in A markedly reduces Fe2+ transport. Simulations indicate that A behaves as an amphipathic helix in the outward-facing state and preferentially stabilizes this conformation over the inward-facing state, thus acting as a key player in controlling conformational equilibrium. This study provides new insights into structural dynamics of Nramps and potentially sheds light on other LeuT-fold transporters.
Matching journals
The top 7 journals account for 50% of the predicted probability mass.
Similar papers in this journal
- Structural insights into the elevator-type transport mechanism of a bacterial ZIP metal transporter 97%
- Molecular insights into substrate translocation in an elevator-type metal transporter 96%
- Asymmetric conformations and lipid interactions shape the ATP-coupled cycle of a heterodimeric ABC transporter 96%
Similar papers in this journal
- Evolution of an interaction between disordered proteins resulted in increased heterogeneity of the binding transition state 96%
- Synergistic computational and experimental studies of a phosphoglycosyltransferase membrane/ligand ensemble 95%
- Biochemical characterization of Bacillus anthracis sortase B: Use in sortase mediated ligation and substrate recognition dependent on residues beyond the canonical pentapeptide binding motif for sortase enzymes 94%
Similar papers in this journal
- Understanding ATP binding to DosS catalytic domain with a short ATP-lid 96%
- Identification of an intrinsically disordered region (IDR) in arginyltransferase 1 (ATE1) 95%
- Comparative Perturbation-Based Modeling of the SARS-CoV-2 Spike Protein Binding with Host Receptor and Neutralizing Antibodies : Structurally Adaptable Allosteric Communication Hotspots Define Spike Sites Targeted by Global Circulating Mutations 94%
"Similar papers" are the closest papers from that journal in the model's embedding space. They show what the match is built on, but the ranking comes mostly from a classifier over the whole training set, not from these examples alone.