A unifying model of T-cell signaling protein condensates in reconstitution experiments

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Abstract

The formation of condensates by the Linker for the Activation of T-cells (LAT) is a key signal gating and amplification step in the T-cell receptor signaling pathway. LAT condensation is challenging to study in-vivo and is therefore often investigated using reconstitution experiments. While these experiments recapitulate key aspects of LAT condensation, they also exhibit some puzzling features. Here, we describe the mechanisms underlying these observations using two complementary models. First, we employ a Smoluchowski aggregation model to show that the delay time before condensation is observed arises from a low effective binding probability between LAT monomers. Second, we propose a field-theoretic model that reproduces all condensate morphologies observed in experiments, showing that they can arise from common underlying dynamics modulated by variations in experimental conditions. This result unifies different experimental observations reported previously. While this article addresses open questions regarding the formation of LAT condensates, our results also provide a common framework for understanding condensation of other multivalent membrane proteins such as EGFR, FGFR2, and nephrin.

Data availability

Microscopy data have been deposited on Zenodo (doi: 10.5281/zenodo.17478868).Model implementations are available on GitHub (https://github.com/YannickOmar/Omar2025_LATReconstitution) and Zenodo (doi: 10.5281/zenodo.17478950).

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Yannick Azhri Din Omar

Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, United States

For correspondence
yadomar@mit.edu

Competing interests
No competing interests declared.

"This ORCID iD identifies the author of this article:" 0009-0000-6700-2519
Simou Sun

Department of Chemistry, Stony Brook University, Stony Brook, United States

Competing interests
No competing interests declared.
Mehran Kardar

Department of Physics, Massachusetts Institute of Technology, Cambridge, United States

For correspondence
kardar@mit.edu

Competing interests
No competing interests declared.
Jay T Groves

Department of Chemistry, University of California, Berkeley, Berkeley, United States

Competing interests
No competing interests declared.

"This ORCID iD identifies the author of this article:" 0000-0002-3037-5220
Arup K Chakraborty

Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, United States

Competing interests
Arup K Chakraborty, While there is no conflict of interest, for completeness it is noted that A.K.C. has equity interest in Flagship Venturelabs VI LLC and Flagship Labs VII LLC, which hold common equity positions in various Flagship portfolio companies, and he also has equity interest in Apriori Bio, Metaphore Bio, and Dewpoint Therapeutics..

"This ORCID iD identifies the author of this article:" 0000-0003-1268-9602

Funding

National Institute of Allergy and Infectious Diseases (2P01AI091580-11A1)

Yannick Azhri Din Omar
Simou Sun
Jay T Groves
Arup K Chakraborty

Novo Nordisk Foundation under the Center for Geometrically Engineered Cellular Systems (NNF17OC0028176)

Simou Sun
Jay T Groves

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Copyright

This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited.