# Spatial Organization of Membrane Signaling

> **NIH NIH R35** · YALE UNIVERSITY · 2023 · $418,750

## Abstract

Project Summary
The overall goal of this project is to understand how the spatial organization of signaling molecules on the cell
membrane regulates signal transduction. Extracellular stimuli are transduced across the plasma membrane,
processed, and amplified along the inner leaflet of the lipid bilayer, and then further delivered into the cytoplasm
and nucleus. It has been shown that proteins and lipids are organized into membrane domains to mediate signal
transduction though the underlying mechanisms are not fully understood. The T cell receptor (TCR) pathway
represents an ideal system for studying this phenomenon. Dozens of the components of the TCR pathway are
enriched in the T cell microcluster, a membrane-associated micron-sized domain that is essential for TCR
signaling. Our recent work suggested that T cell microclusters are phase-separated condensates driven by
multivalent protein-protein interactions. What is lacking, however, is an understanding of how the formation of
these microclusters is regulated by the local membrane environment, where significant changes occur in both
lipid composition and membrane geometry upon TCR activation. Therefore, this proposal aims to determine the
mechanism by which lipids and membrane geometry regulate the assembly of T cell microclusters and the
associated functional consequences during T cell activation. The following questions will be addressed: How do
charged lipids modulate T cell microcluster formation? How does membrane geometry influence microcluster
function? How do microclusters affect T cells’ killing activity? Answering these questions will significantly impact
the field because it will reveal how the protein machineries and lipid bilayers coordinate to process and amplify
the signal from antigen stimuli to cell activation. Moreover, the majority of currently identified phase-separated
structures are 3-D droplets located in the nucleus or cytoplasm whereas T cell microclusters are 2-D domains
on the membrane. Understanding the functional relationship between T cell microclusters and lipid bilayers is
expected to create a new research interface between the field of protein self-assembly and membrane signaling.

## Key facts

- **NIH application ID:** 10649716
- **Project number:** 5R35GM138299-04
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** Xiaolei Su
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $418,750
- **Award type:** 5
- **Project period:** 2020-08-01 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10649716

## Citation

> US National Institutes of Health, RePORTER application 10649716, Spatial Organization of Membrane Signaling (5R35GM138299-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10649716. Licensed CC0.

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