# Maintenance of brain homeostasis by an ancient zinc metallochaperone

> **NIH NIH K99** · VANDERBILT UNIVERSITY MEDICAL CENTER · 2024 · $123,617

## Abstract

SUMMARY
 Zinc binding metalloproteins and metalloenzymes constitute ≈10% of the vertebrate metalloproteome
and are essential for many cellular processes. Due to the critical importance of zinc to vertebrate physiology,
zinc deficiency leads to numerous pathologies and is involved in the pathogenesis of many neurological
disorders. In fact, zinc is one of the most prevalent metal ions in the brain where it serves important roles in
neurogenesis, neuronal migration, and differentiation. Zinc deficiency constitutes a pervasive public health
problem considering that approximately half of the world's population suffers from dietary zinc deficiency, now
the fifth most important risk factor for mortality in developing countries. Despite the known importance of zinc
cofactors to cellular function, the mechanisms by which zinc levels regulate tissue homeostasis remains poorly
defined.
 Cellular zinc homeostasis is modulated by a specialized family of zinc trafficking proteins called
metallochaperones. It is speculated that metallochaperones facilitate the hierarchical delivery of metals to their
client proteins thereby regulating cellular and organismal homeostasis. We have identified the first vertebrate
zinc metallochaperone, which we recently named Zinc regulated GTPase metalloprotein activator 1 (ZNG1). We
demonstrated that vertebrate ZNG1 binds to and transfers zinc to metalloproteins to promote their enzymatic
activity. Further, we identified numerous candidate ZNG1 client zinc metalloproteins in zebrafish and mice that
are associated with brain function, including the zinc-finger transcription factors, ZFHX3 and ZFHX4. Collectively
these findings suggest that ZNG1 is a regulator of brain development and function via interactions with specific
Zn-requiring transcription factors, which will be tested by experiments proposed in this application.
 This work is expected to determine the impact of ZNG1 mediated zinc transfer on transcription factor
activity in the brain (Aim 1) while defining the ZNG1-dependent ZFHX3 and ZFHX4 signaling pathways important
for neuronal development, neuronal response to stress, and behavior (Aim 2). Completion of these aims has the
potential to identify ZNG1 as a factor that modulates signaling in the brain in a manner that is dependent upon
zinc bioavailability. These findings will shed light on the in vivo role of the first discovered zinc metallochaperone
and will vertically advance our understanding of zinc homeostasis and contributions to the progression of human
neurological disorders.

## Key facts

- **NIH application ID:** 10886230
- **Project number:** 1K99GM151477-01A1
- **Recipient organization:** VANDERBILT UNIVERSITY MEDICAL CENTER
- **Principal Investigator:** Caitlin Cynthia Murdoch
- **Activity code:** K99 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $123,617
- **Award type:** 1
- **Project period:** 2024-05-01 → 2026-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10886230

## Citation

> US National Institutes of Health, RePORTER application 10886230, Maintenance of brain homeostasis by an ancient zinc metallochaperone (1K99GM151477-01A1). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10886230. Licensed CC0.

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