# Structural Flexibility Mediates Circadian Adaptation in Diverse Organisms

> **NIH NIH R15** · SOUTHERN METHODIST UNIVERSITY · 2021 · $425,609

## Abstract

Project Summary:
Circadian clocks have evolved to synchronize organism physiology with environmental conditions. Central to
their function is the ability to adapt to unique environmental niches to maintain a 24-hour daily cycle to optimize
organism fitness. Although circadian networks differ in various organisms, two hallmarks of circadian networks
are conserved across phyla: 1) A central oscillator composed of a transcription-translation feedback loop (TTFL),
and 2) Sensory elements that entrain the TTFL to endogenous and environmental cues. Examination of circadian
network topology across diverse organisms reveals two protein domain families are widely employed to integrate
environmental stimuli into circadian networks. These are members of the Light-Oxygen-Voltage (LOV: fungi and
plants) and Cryptochromes (CRY: plants and animals). Results in diverse organisms demonstrate that despite
conservation, the mechanisms and roles of these proteins can differ considerably. How LOV and CRY proteins
are able to adapt the magnitude and mode of signal propagation to adapt to environmental conditions is unknown.
Based on recent computational and biophysical studies of LOV and CRY systems in plants, fungi, and animals,
we hypothesize that LOV/CRY systems leverage a dynamic conformational landscape to enable
integration of environmental variables that are species and/or environment specific. By understanding
these complex landscapes, we can: 1) Predict how closely related organisms tune circadian responses to
maximize fitness. 2) Develop strategies to manipulate organism physiology to rectify either deleterious (disease
causing) errors or encourage beneficial adaptations. Herein, we develop a platform, amendable to
undergraduate researchers, that integrates biological, biophysical, and computational approaches. We focus on
two aims to verify plasticity in circadian networks. We specifically focus on systems that retain allosteric
mechanisms analogous to those found in mammals, thereby allowing us to develop new strategies to impact
human disease. Aim 1: Leveraging recent computational and structural data we will directly evaluate allosteric
switch residues that alter the conformational landscape of LOV proteins. Specific focus will be on residues
allowing closely related plant and fungal species to alter signaling dynamics in an environmentally specific
manner. We will demonstrate tunability of these signaling networks, thereby developing new methodologies to
manipulate organism physiology. Aim 2: Leveraging recent chemical and structural studies of a photoactive
vertebrate CRY, we will demonstrate that analogous structural plasticity exists in CRY-based systems allowing
organisms to alter the magnitude and direction of conformational responses. Using structural and biochemical
approaches we will develop an optogenetic tool capable of manipulating mammalian circadian networks. The
combined approach enables us to identify natural mechanisms employed to tune c...

## Key facts

- **NIH application ID:** 10291972
- **Project number:** 2R15GM109282-03
- **Recipient organization:** SOUTHERN METHODIST UNIVERSITY
- **Principal Investigator:** Brian David Zoltowski
- **Activity code:** R15 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $425,609
- **Award type:** 2
- **Project period:** 2014-08-01 → 2025-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10291972

## Citation

> US National Institutes of Health, RePORTER application 10291972, Structural Flexibility Mediates Circadian Adaptation in Diverse Organisms (2R15GM109282-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10291972. Licensed CC0.

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