# Antioxidant signaling by protein AMPylation

> **NIH NIH R01** · UT SOUTHWESTERN MEDICAL CENTER · 2020 · $322,979

## Abstract

Project Summary
We have discovered that the predicted inactive pseudokinase selenoprotein O (SelO) adopts an atypical protein
kinase fold, yet transfers AMP instead of phosphate to protein substrates in a post translational modification
known as AMPylation. Our results illustrate the catalytic versatility of the protein kinase superfamily and suggest
that AMPylation may be a more widespread post translational modification than previously appreciated. SelO
localizes to the mitochondria, AMPylates proteins involved in cellular metabolism and redox biology, and appears
to regulate an ancient and highly conserved cellular antioxidant signaling pathway. In higher eukaryotes, SelO
contains the 21st genetically encoded amino acid, selenocysteine, which we propose functions as a redox sensor
to regulate SelO activity in response to oxidative stress.
Although reactive oxygen species are an obligatory part of human biology, elevated levels are characteristic of
many disease states. For example, elevated reactive oxygen species can lead to DNA damage, which can
initiate oncogenic transformation leading to cancer. Furthermore, alterations in redox homeostasis are
implicated in the pathology of conditions such as stroke, heart attack, and peripheral vascular disease, all of
which are major contributors to morbidity and mortality in United States. Therefore, a mechanistic understanding
of the pathways that protect cells from oxidative stress could have major impacts on human health and disease.
The major goal of this proposal is to determine the molecular mechanisms by which SelO-dependent AMPylation
of mitochondrial proteins protects cells from oxidative stress and regulates redox homeostasis. As part of this
work, we will determine the functional consequences of SelO-catalyzed AMPylation of a subset of substrates as
well as the structural basis for the redox-dependent regulation of SelO activity. We anticipate that the results
obtained herein will have the potential to define new paradigms of cellular regulation and redox signaling and
could lead to innovative diagnostic tools or novel approaches for the treatment of human diseases.

## Key facts

- **NIH application ID:** 9860880
- **Project number:** 1R01GM135189-01
- **Recipient organization:** UT SOUTHWESTERN MEDICAL CENTER
- **Principal Investigator:** Vincent Scott Tagliabracci
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $322,979
- **Award type:** 1
- **Project period:** 2020-02-01 → 2024-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9860880

## Citation

> US National Institutes of Health, RePORTER application 9860880, Antioxidant signaling by protein AMPylation (1R01GM135189-01). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9860880. Licensed CC0.

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