# Mechanism of Divalent Metal Transport by Nramp-Family Transporters

> **NIH NIH R01** · HARVARD UNIVERSITY · 2022 · $372,622

## Abstract

PROJECT SUMMARY - Mechanism of Divalent Metal Transport by Nramp-Family Transporters
Background: Metals like iron and manganese are essential to many physiological processes
including oxygen transport and energy metabolism. But excess or deficiency of these ions leads
to health issues—including anemia, hemochromatosis and immune or neurological disorders—
and their physiological levels are thus tightly regulated. Nramps (natural resistance-associated
macrophage proteins) are symporters that import metal ions and protons into cells, and thus are
crucial to maintaining transition metal homeostasis. However, the mechanism of coupling
between metal ions and protons is unclear. Structures of bacterial Nramps revealed the binding
site for the transition metal ion substrate and a proton pathway formed by a polar residue network
in the protein scaffold. Furthermore, evidence is emerging that distant Nramp homologs have
variations of the metal-binding sequence motifs and transport other metals like Al3+ and Mg2+.
Proposed Research: Our goal is two-fold: (i) develop an atomic-level biophysical understanding
of the canonical mechanistic features shared by most eukaryotic and bacterial Nramps; and (ii)
contrast these features to those in more distant Nramp-like homologs. We combine sequence
bioinformatics and other computational approaches with structural and biochemical analyses. In
Aim 1, we investigate canonical features of Nramp transporters using a well-established bacterial
Nramp model system. We will determine (1a) the metal ion coordination geometry and affinity and
selectivity determinants, (1b) whether proton transport is thermodynamically coupled to metal
transport, and (1c) how protonation states of the protein alter conformational dynamics. In Aim 2,
we investigate divergent Nramp homologs with noncanonical metal-binding and proton-pathway
sequence motifs. We examine how these sequence changes affect (2a) proton transport, (2b)
metal selectivity, and (2c) metal coordination geometries. Our two aims synergize to provide in-
depth biophysical mechanisms and a broad perspective of this important family of transporters.
Impact: Both bacterial and mammalian Nramps impact human health. In bacteria, Nramps help
commensal microbes acquire essential transition metals and promote colonization by pathogens.
Human Nramps are essential for immunity to intracellular pathogens, liver and blood homeostasis,
and brain function. This research on metal ion transport by Nramps provides the biochemical and
biophysical grounding necessary to explain their essential role in metal homeostasis at the cellular
and organismal level. This knowledge could lead to better therapies for metal-related diseases
including anemia, hemochromatosis, and many immune and neurological disorders.

## Key facts

- **NIH application ID:** 10434927
- **Project number:** 5R01GM120996-06
- **Recipient organization:** HARVARD UNIVERSITY
- **Principal Investigator:** RACHELLE GAUDET
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $372,622
- **Award type:** 5
- **Project period:** 2017-01-01 → 2025-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10434927

## Citation

> US National Institutes of Health, RePORTER application 10434927, Mechanism of Divalent Metal Transport by Nramp-Family Transporters (5R01GM120996-06). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10434927. Licensed CC0.

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