# Metalloregulation by MerR and Fur Protein Families

> **NIH NIH R01** · NORTHWESTERN UNIVERSITY · 2020 · $376,753

## Abstract

Summary
A number of new principles have emerged from the study of inorganic physiology, including the
idea that intracellular metals such as zinc, copper and iron are not `trace elements' from a
cellular point of view. Metallome analysis for many cell types reveals that essential metal ions
are routinely maintained in most cells at much higher levels (i.e., 0.6 mM). These insights, as
well as the emerging literature linking metal physiology to many disease states, underscore the
importance of establishing the fundamental principles, general pathways and macromolecular
mechanisms required to manage cellular regulation of millions of metal ions. Our approach to
delineating these new principles involves mechanistic and structural characterization of metal
receptors that switch on and off genes in a metal dependent manner. This proposal addresses
several issues in the field of inorganic physiology. The first question is: how do regulatory
metal receptors work within the larger macromolecular complexes that they control, including
the multisubunit enzymes RNA polymerase and the ribosome? Our preliminary work indicates
that copper and zinc homeostasis in E. coli is under the control of complex transcriptional and
translational mechanisms that involve protein-induced distortions in DNA structure. The
proposed studies also employ advanced sequencing and quantitative proteomic technology to
understand how cells control the overall metal economy. This work is revealing many new
metal responsive genes in E. coli, which in turn informs our knowledge of fundamental
mechanisms used by pathogens when they are subjected to metal limitation by the host
immune system. The specific aims focus on resolving fundamental questions about the
structures, functions and molecular mechanisms of these key metal sensing metalloregulatory
proteins. The proposed experimental approach will employ x-ray crystallography, biophysical
methods, single particle electron microscopy, and proteomic and bioinformatic methods to
understand the pathways that E. coli uses to respond to changing metal ion levels in the
growth media. The effects of these biophysical switching mechanisms on intracellular metal
physiology will then be examined using novel single cell analytical and imaging methods with
the overarching goal of establishing general principles and mechanisms that control metal ion
homeostasis in normal and disease states.

## Key facts

- **NIH application ID:** 9822973
- **Project number:** 5R01GM038784-31
- **Recipient organization:** NORTHWESTERN UNIVERSITY
- **Principal Investigator:** THOMAS V O'HALLORAN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $376,753
- **Award type:** 5
- **Project period:** 1987-07-01 → 2022-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9822973

## Citation

> US National Institutes of Health, RePORTER application 9822973, Metalloregulation by MerR and Fur Protein Families (5R01GM038784-31). Retrieved via AI Analytics 2026-06-01 from https://api.ai-analytics.org/grant/nih/9822973. Licensed CC0.

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