An N-terminal amphipathic helix governs activity and conformational dynamics of Nramp metal transporters
Year: 2026
Type: article
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 (αA) 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 αA. Our results show that deletion or substitution of conserved residues in αA markedly reduces Fe 2+ transport. Simulations indicate that αA 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.
Source: Journal of Biological Chemistry
Institution: Michigan State University
Language: English
Subfield: Hematology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $3,430
Funders: Foundation for the National Institutes of Health, U.S. Department of Agriculture, Michigan State University, Murray State University, National Institutes of Health, National Institute of Food and Agriculture, College of Engineering, Michigan State University, National Institute of General Medical Sciences
OpenAlex ID: W7164043707