# Capturing structure and dynamics of transmembrane signaling proteins

> **NIH NIH R01** · UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN · 2023 · $308,390

## Abstract

Project Summary
To sense the environment, cells rely on membrane-embedded receptors. The receptor tyrosine kinase (RTK)
family of signaling proteins is large, diverse, and centrally important both to human development diseases and
cancers. Evidence so far supports a model that signal passage through RTKs is initiated by a structural change
in the extracellular domain and then conducted through the transmembrane (TMD) and juxtamembrane (JMD)
domains to the cytoplasmic kinase domain. The receptors usually are activated in the dimer form. Numerous
RTK mutations confer diseases, e.g. single point mutations in ~30% of residues of the TMD of the fibroblast
growth factor receptor 3 (FGFR3) are pathogenic, while mutations of tropomyosin receptor kinase A can lead
to cancers. Understanding the structural interactions of the FGFR3 and TrkA signaling TMD and JMD therefore
is crucial for fundamental biology and for future development of therapies that may target these pathways.
Atomistically resolved TMD+JMD dimer structures are the major objective of this project. Application of
traditional computational and crystallographic methods is hindered by the fluid nature of the membrane
environment. Our goal is to develop novel efficient computational methods that guide and maximally leverage
NMR, FRET, and in-cell experimental data and apply these methods to capture the FGFR3 and TrkA TMD and
TMD+JMD dimer structures for the wild type and mutated pathogenic forms. In Aim 1, we will combine our
novel highly mobile membrane mimetic model, capable of spontaneously capturing candidate TMD dimer
structures, with a novel minimally biased way of applying a reduced number of computational restraints based
on experimental distance measurements. The resulting TMD dimer structures will be validated by comparing
computed and experimentally measured parameters. These structures will reveal the role mutations play in
RTK dynamics. In Aim 2, we will use our computational-experimental approach to determine the role that
juxtamembrane domains play in RTK signaling. The resolved structures of the mutated dimers will facilitate
understanding of the pathology and mechanisms of receptor activation. Our novel computational approaches
combined with extended expertise of co-investigators and collaborators in NMR, FRET, RTK signaling, and
membrane-associated phenomena, uniquely position us to develop and apply this methodology. We will also
develop an open-source, user friendly workflow plugin for a widely-used software suite that will allow efficient
use of the proposed protocols by the scientific community. Completion of the specific aims will increase our
ability to efficiently gain structural information on RTKs and will open new research avenues for investigating
mechanisms of transmembrane signaling in health and disease leading to development of new treatments.

## Key facts

- **NIH application ID:** 10673717
- **Project number:** 5R01GM141298-03
- **Recipient organization:** UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN
- **Principal Investigator:** Taras V. Pogorelov
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $308,390
- **Award type:** 5
- **Project period:** 2021-09-20 → 2025-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10673717

## Citation

> US National Institutes of Health, RePORTER application 10673717, Capturing structure and dynamics of transmembrane signaling proteins (5R01GM141298-03). Retrieved via AI Analytics 2026-06-11 from https://api.ai-analytics.org/grant/nih/10673717. Licensed CC0.

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