# Principles of selectivity and translocation in transition metal transporter

> **NIH NIH R35** · UNIVERSITY OF TEXAS DALLAS · 2021 · $380,661

## Abstract

Abstract
Transition metals are essential trace elements for life, playing pivotal roles in biochemical processes. First-row
transition metals, such as iron, copper, and zinc, play fundamental catalytic, structural and signaling functions.
Their concentrations are tightly regulated to meet indispensable cellular requirements without reaching toxic
levels. On the other hand, non-essential second-/third-row transition metal complexes are toxic to cells and
exploited as therapeutic molecules. A gatekeeper role in controlling metal concentrations in all cells is mediated
by transmembrane transporters that regulate the vectorial metal uptake and extrusion across cellular
membranes. The principles underlying metal selectivity and molecular mechanism of transport by these
nanomachines remain elusive.
This MIRA application targets the study of primary active transition metal pumps and solute carriers (SLC) and
will focus on: (i) investigating the principles of metal selectivity for first, second- and third- row transition metals
and (ii) their metal coordination chemistry; (iii) determining the metal translocation pathway; (iv) addressing the
mechanisms of energy transduction processes at a molecular level.
My laboratory has developed an integrated chemical, biophysical, and structural approach to determine how
metal selection and transport occurs in different metal transporter families. With this multidisciplinary strategy,
we will target known and novel transporter families involved in metal homeostasis and in disease progression;
specifically: 1) P1B-type ATPases, primary active transporters controlling intracellular copper levels in humans,
and modulating the concentrations of copper and other transition metals in pathogenic bacteria; 2) TMEM205, a
novel human transporter potentially involved in copper extrusion and responsible for anti-cancer Pt-complexes
transport and resistance; 3) IroT transporters, putative iron-regulated solute carriers responsible for iron(II)
acquisition and virulence in pathogenic prokaryotes.
We will couple biophysical, spectroscopic, and structural studies on purified, detergent-solubilized transporters
to the characterization in proteoliposomes, where the transporters are embedded in a native-like lipid bilayer. By
encapsulating in the proteoliposomes metal-dependent fluorescence chelators, sensors for secondary ions, and
probes for membrane potential, we will develop an in vitro tool for monitoring real-time substrate translocation in
a membrane environment. This platform establishes an innovative framework to address i) the metal substrate
selectivity, ii) the nature of cotransported ions, iii) their relative stoichiometry, iv) the electrogenic properties, and
v) the role of membrane potential on catalytic metal translocation.
The project targets a neglected aspect of bioinorganic chemistry towards the understanding of the principles
controlling metal translocation across membranes. Besides shading light on the basic mol...

## Key facts

- **NIH application ID:** 10194543
- **Project number:** 5R35GM128704-04
- **Recipient organization:** UNIVERSITY OF TEXAS DALLAS
- **Principal Investigator:** Gabriele Meloni
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $380,661
- **Award type:** 5
- **Project period:** 2018-07-01 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10194543

## Citation

> US National Institutes of Health, RePORTER application 10194543, Principles of selectivity and translocation in transition metal transporter (5R35GM128704-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10194543. Licensed CC0.

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