# Molecular Mechanisms of Copper Transport

> **NIH NIH R01** · WASHINGTON UNIVERSITY · 2020 · $344,531

## Abstract

ABSTRACT
Molecular Mechanisms of Copper Transport
Copper (Cu) is an essential trace element for growth and development because Cu acts as an indispensable
cofactor for a variety of enzymes that are involved in multiple biological processes, and mutations of genes
involved in Cu transport result in severe, even lethal, neurodegenerative diseases such as Wilson's disease
and Menkes syndrome. Abnormal Cu levels have also been linked to a range of pathological conditions,
including Alzheimer's, Parkinson's, cardiovascular disease and cancer. Despite the overwhelming importance
of Cu in health and disease, we have only rudimentary understanding of the molecular basis of Cu transport,
with a lack of high-resolution three-dimensional structures and relevant biochemical and biophysical
characterization that are essential for the development of appropriate mechanism-based therapeutics.
Therefore, our long-term goal is to attain a comprehensive understanding of molecular mechanisms of Cu
homeostasis using a combination of biochemical, biophysical, and structural approaches. In cells, appropriate
Cu levels are tightly regulated by a sophisticated network of Cu-handling proteins, including Cu transporters,
chaperones, and acceptors, to control the acquisition, distribution, and delivery of bioavailable Cu. Ubiquitous
in eukaryotes, the copper transporter (Ctr) family of integral membrane proteins, Ctr1 and Ctr2, is involved in
Cu transport across cellular membranes including both the plasma and intracellular organelle membranes. We
have recently developed innovative methods for large-scale production of Ctr1 and Ctr2 transporter proteins,
generation of diffraction-quality crystals, and for successful in vitro reconstitution assays. With these exciting
preliminary developments, we are now able to combine X-ray crystallography, in vitro biochemical
reconstitution, in vivo functional complementation assays, and site-directed mutagenesis to address Cu
transport mechanisms. Specifically, we aim to determine the molecular basis of selectivity and permeation in
Cu uptake by Ctr1, the underlying mechanism of zinc regulation in Ctr1, and molecular determinants for Cu
transport in Ctr proteins. Our proposed work will provide atomic structures of Ctr1 and Ctr2 transporters in
multiple functional states and uncover structural and molecular mechanisms of Cu transport. Detailed
understanding of the mechanism, function, and regulation of Ctr proteins will open new therapeutic avenues for
the treatment of a broad spectrum of diseases associated with disturbed Cu metabolism.

## Key facts

- **NIH application ID:** 9934304
- **Project number:** 5R01NS109307-03
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** Peng Yuan
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $344,531
- **Award type:** 5
- **Project period:** 2018-09-30 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9934304

## Citation

> US National Institutes of Health, RePORTER application 9934304, Molecular Mechanisms of Copper Transport (5R01NS109307-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9934304. Licensed CC0.

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