Spatial Organization of Membrane Signaling

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Principal Investigator: Xiaolei  Su
Organization: YALE UNIVERSITY
Fiscal Year: 2024
Award: $418,750
Funding agency: National Institute of General Medical Sciences

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.

Terms: <3-D structure><3-dimensional structure><3D structure><Address><Affect><Antigens><Basic Research><Basic Science><Biological Function><Biological Process><Cell Body><Cell Communication and Signaling><Cell Nucleus><Cell Signaling><Cell membrane><Cells><Charge><Cytoplasm><Cytoplasmic Membrane><Disease><Disorder><Environment><Foundations><Geometry><Goals><Immune response><Immunological response><Infection><Inner Leaflet of the Lipid Bilayer><Intracellular Communication and Signaling><Lipid Bilayers><Lipids><MHC Receptor><Major Histocompatibility Complex Receptor><Mediating><Membrane><Mission><NIGMS><National Institute of General Medical Sciences><Nucleus><Pathway interactions><Phase><Physical condensation><Plasma Membrane><Process><Proteins><Public Health><Receptor Activation><Receptor Signaling><Research><Signal Transduction><Signal Transduction Systems><Signaling><Signaling Molecule><Stimulus><System><T-Cell Activation><T-Cell Antigen Receptors><T-Cell Receptor><T-Cells><T-Lymphocyte><Work><activate T cells><biological signal transduction><cancer progression><cell killing><condensation><extracellular><host response><immune system response><immunogen><immunoresponse><lipid bilayer membrane><membrane structure><neoplasm progression><neoplastic progression><pathogen><pathway><plasmalemma><protein protein interaction><self assembly><three dimensional structure><thymus derived lymphocyte><tumor progression>