# Structural and mechanistic studies of PAS sensing

> **NIH NIH R01** · ADVANCED SCIENCE RESEARCH CENTER · 2022 · $361,100

## Abstract

ABSTRACT
For cells to properly adapt to changing environmental conditions around them, they must rely on sensory
proteins which both detect these changes and initiate proper responses. As one solution to this challenge,
nature has evolved classes of ligand-regulated protein/protein interaction domains, harnessing these to control
numerous types of protein function. Understanding how these domains undertake the requisite sensing and
signaling events has given insight into fundamental aspects of biology, enabled the development of new tools
for biomedical research, and inspired novel therapies to disease. Here we focus on examining the signaling
mechanisms used by proteins containing PAS (Period-ARNT-Singleminded) domains, found in tens of
thousands of proteins where they control the activity of over 20 enzymatic and non-enzymatic effector
domains. These processes are regulated by different stimuli in different members of the family, harnessing
changes in the occupancy or configuration of bound cofactors to “switch” activity on and off. Some aspects of
these triggers are well understood in some PAS domains, such as in the subset known as LOV (Light-Oxygen-
Voltage) photosensory domains, where blue light illumination drives the specific photochemical formation of
protein/flavin adducts which allosterically controls protein conformation around the chromophore. However,
fundamental questions regarding these signaling processes remain unanswered, limiting our understanding of
how environmental changes are sensed and how these might be artificially controlled. We propose to answer
these limitations by pursuing three aims: 1). Determine activation-associated structural changes of several
classes of bacterial LOV and PAS proteins; 2). Examine the generality of LOV signaling within a novel class of
fungal RGS-LOV proteins; 3). Examine PAS regulation of serine/threonine kinase activity in the nutrient-
sensing human PAS kinase. To achieve these ends, we will take advantage of a broad foundation of
preliminary structural and functional data that will be extended with a mix of biophysical and biochemical
studies. Outcomes from this research will include information about fundamental regulatory processes
employed by these proteins, giving insights into both basic aspects of biomedicine along with potential
therapeutic and biotechnology applications.

## Key facts

- **NIH application ID:** 10436974
- **Project number:** 5R01GM106239-11
- **Recipient organization:** ADVANCED SCIENCE RESEARCH CENTER
- **Principal Investigator:** Kevin H Gardner
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $361,100
- **Award type:** 5
- **Project period:** 2013-09-30 → 2025-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10436974

## Citation

> US National Institutes of Health, RePORTER application 10436974, Structural and mechanistic studies of PAS sensing (5R01GM106239-11). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10436974. Licensed CC0.

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