# Capturing structure and dynamics of transmembrane signaling proteins

> **NIH NIH R01** · UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN · 2022 · $113,210

## Abstract

Project Summary of the Funded Award (R01GM141298)
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:** 10582241
- **Project number:** 3R01GM141298-01A1S1
- **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:** 2022
- **Award amount:** $113,210
- **Award type:** 3
- **Project period:** 2021-09-20 → 2025-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10582241

## Citation

> US National Institutes of Health, RePORTER application 10582241, Capturing structure and dynamics of transmembrane signaling proteins (3R01GM141298-01A1S1). Retrieved via AI Analytics 2026-06-11 from https://api.ai-analytics.org/grant/nih/10582241. Licensed CC0.

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