# The Cellular Environment as a Regulator of Intrinsically Disordered Proteins

> **NIH NIH R35** · UNIVERSITY OF CALIFORNIA, MERCED · 2023 · $371,965

## Abstract

Project Summary
We propose to study the effects of the chemical composition of the environment on the structure
and function of intrinsically disordered proteins in the test tube and in the cell. The cellular
environment is dynamic and heterogeneous in both space and time, and far removed from the
idealized buffers commonly used in biochemistry experiments. How proteins function in this
environment is a fundamental question in biology that is poorly understood. Especially puzzling
are intrinsically disordered proteins, which make up over 30% of the human proteome and play a
disproportionately large role in cellular regulation and misregulation. Intrinsically disordered
proteins do not adopt a single native structure. Instead, they exist as an ensemble of
conformations that have large surface areas and a low number of intramolecular bonds, making
them highly susceptible to changes in solution composition. Why has evolution selected this
malleable subset of proteins to act as central hubs and regulators of cellular function when routine
cell cycle changes can alter their activity? Our lab aims to understand how disordered proteins
function and interact in the complex cellular environment, and how the chemical composition of
this environment can act as a master regulator that tunes their function. In order to do this, we
use a multi-scale approach that combines all-atom simulations, high-throughput biophysical
methods, and live cell microscopy. This bottom up study is designed to reveal the physical-
chemical rules governing how solution-protein interactions affect protein structure and function.
The broad goals of our work are (1) to gain a molecular-level understanding of how solution
composition controls disordered protein structure and binding in the test tube and inside the cell;
(2) to develop tools to control the chemical composition in the cell, and use this control to alter
protein function; and (3) to identify and characterize the functional mechanisms of proteins that
evolved to act as sensors and actuators of the cellular environment. The proposed work aims to
uncover an entirely new ubiquitous regulation mechanism. Successful completion will uncover the
underlying driving forces behind this solution-driven regulation, identify the proteins affected by it,
and provide researchers with tools to leverage it towards control of cellular pathways. Most
importantly, our findings will be based on physical chemistry principles, and so will not be
organism-specific, and apply to a wide range of biomolecules, organisms, and ecosystems.

## Key facts

- **NIH application ID:** 10629326
- **Project number:** 5R35GM137926-04
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, MERCED
- **Principal Investigator:** Shahar Sukenik
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $371,965
- **Award type:** 5
- **Project period:** 2020-08-01 → 2025-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10629326

## Citation

> US National Institutes of Health, RePORTER application 10629326, The Cellular Environment as a Regulator of Intrinsically Disordered Proteins (5R35GM137926-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10629326. Licensed CC0.

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