Biology subjects

Omar, Y. A. D.

Publications and source records attributed to Omar, Y. A. D..

3 recordsLinked to original sources

bioRxiv2026

LAT condensation gates PLCγ1 activation via bimodal LAT phosphorylation

T cells can respond to even a single molecular binding event of antigen to a TCR. A key step in the TCR signaling pathway that definitively exhibits this single molecule response is the initiation of calcium influx by activation of PLC{gamma}1 in the LAT protein condensate. Here, we describe detailed kinetic measurements examining how protein condensation of LAT regulates activation of PLC{gamma}1 using a reconstituted membrane system. The results reveal that membrane recruitment of PLC{gamma}1 is tightly controlled by the LAT phosphorylation state, with no measurable independent recruitment to PIP2 or PIP3 lipids via the PLC{gamma}1 PH domains. We further observe PLC{gamma}1 is rapidly activated by membrane-associated kinase upon recruitment, irrespective of the LAT condensation state. These studies also revealed a crosstalk mechanism in which the TEC family kinases responsible for PLC{gamma}1 activation also phosphorylate LAT. This interaction establishes a positive feedback loop in LAT phosphorylation, mediated through LAT condensation, which drives a bimodal LAT phosphorylation response to TCR activation. Kinetic modeling reveals how this LAT phosphorylation response can cooperatively gate PLC{gamma}1 activation from a single TCR. These results suggest the LAT condensate facilitates both signal amplification and noise suppression in PLC{gamma}1 activation through a bimodal switch affecting LAT phosphorylation. Significance StatementT cells are sensitive sensors capable of detecting and responding to trace amounts of foreign antigen. Understanding how they achieve such sensitivity while maintaining accurate antigen discrimination remains a key challenge. Here, through detailed kinetic measurements of PLC{gamma}1 activation, we identify a cross reactivity in which kinases responsible for PLC{gamma}1 phosphorylation also phosphorylate LAT. This creates a bimodal switch controlling LAT phosphorylation levels, which gates PLC{gamma}1 activation from single TCR signals. We suggest this mechanism plays a key role in the signal amplification and noise suppression required for T cells to detect single antigen molecules.

biophysics↗

bioRxiv2025

A unifying model of LAT condensates in reconstitution experiments

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.

biophysics↗

bioRxiv2019

Non-axisymmetric shapes of biological membranes from locally induced curvature

In various biological processes such as endocytosis and caveolae formation, the cell membrane is locally deformed into curved configurations. Previous theoretical and computational studies to understand membrane morphologies resulting from locally induced curvature are often limited to axisymmetric shapes, which severely restricts the physically admissible morphologies. Under the restriction of axisymmetry, past efforts predict that the cell membrane buds at low resting tensions and stalls at a flat pit at high resting tensions. In this work, we lift the restriction of axisymmetry by employing recent theoretical and numerical advances to understand arbitrarily curved and deforming lipid bilayers. Our non-axisymmetric morphologies reveal membrane morphologies which agree well with axisymmetric studies--however only if the resting tension of the membrane is low. When the resting tension is moderate to high, we show that (i) axisymmetric invaginations are unstable; and (ii) non-axisymmetric ridge-shaped structures are energetically favorable. We further study the dynamical effects resulting from the interplay between intramembrane viscous flow and induced curvature, and find the rate at which the locally induced curvature increases is a key determinant in the formation of ridges. In particular, we show that axisymmetric buds are favored when the induced curvature is rapidly increased, while non-axisymmetric ridges are favored when the curvature is slowly increased: The rate of change of induced curvature affects the intramembrane viscous flow of lipids, which can impede the membranes ability to transition into ridges. We conclude that the appearance of non-axisymmetric ridges indicates that axisymmetry cannot be generally assumed when understanding processes involving locally induced curvature. Our results hold potentially relevant implications for biological processes such as endocytosis, and physical phenomena like phase separation in lipid bilayers.

biophysics↗