Kinetic frustration by limited bond availability controls the LAT protein condensation phase transition on membranes
LAT is a membrane-linked scaffold protein that undergoes a phase transition to form a two-dimensional protein condensate on the membrane during T cell activation. Governed by tyrosine phosphorylation, LAT recruits various proteins that ultimately enable condensation through a percolation network of...
| Main Authors: | , , , |
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| Other Authors: | |
| Format: | Journal Article |
| Language: | English |
| Published: |
2023
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| Subjects: | |
| Online Access: | https://hdl.handle.net/10356/170826 |
| _version_ | 1811688670902616064 |
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| author | Sun, Simou GrandPre, Trevor Limmer, David T. Groves, Jay T. |
| author2 | Institute for Digital Molecular Analytics and Science (IDMxS) |
| author_facet | Institute for Digital Molecular Analytics and Science (IDMxS) Sun, Simou GrandPre, Trevor Limmer, David T. Groves, Jay T. |
| author_sort | Sun, Simou |
| collection | NTU |
| description | LAT is a membrane-linked scaffold protein that undergoes a phase transition to form a two-dimensional protein condensate on the membrane during T cell activation. Governed by tyrosine phosphorylation, LAT recruits various proteins that ultimately enable condensation through a percolation network of discrete and selective protein-protein interactions. Here, we describe detailed kinetic measurements of the phase transition, along with coarse-grained model simulations, that reveal that LAT condensation is kinetically frustrated by the availability of bonds to form the network. Unlike typical miscibility transitions in which compact domains may coexist at equilibrium, the LAT condensates are dynamically arrested in extended states, kinetically trapped out of equilibrium. Modeling identifies the structural basis for this kinetic arrest as the formation of spindle arrangements, favored by limited multivalent binding interactions along the flexible, intrinsically disordered LAT protein. These results reveal how local factors controlling the kinetics of LAT condensation enable formation of different, stable condensates, which may ultimately coexist within the cell. |
| first_indexed | 2024-10-01T05:35:54Z |
| format | Journal Article |
| id | ntu-10356/170826 |
| institution | Nanyang Technological University |
| language | English |
| last_indexed | 2024-10-01T05:35:54Z |
| publishDate | 2023 |
| record_format | dspace |
| spelling | ntu-10356/1708262023-10-18T15:31:59Z Kinetic frustration by limited bond availability controls the LAT protein condensation phase transition on membranes Sun, Simou GrandPre, Trevor Limmer, David T. Groves, Jay T. Institute for Digital Molecular Analytics and Science (IDMxS) Science::Chemistry Amino Acids Protein-Protein Interactions LAT is a membrane-linked scaffold protein that undergoes a phase transition to form a two-dimensional protein condensate on the membrane during T cell activation. Governed by tyrosine phosphorylation, LAT recruits various proteins that ultimately enable condensation through a percolation network of discrete and selective protein-protein interactions. Here, we describe detailed kinetic measurements of the phase transition, along with coarse-grained model simulations, that reveal that LAT condensation is kinetically frustrated by the availability of bonds to form the network. Unlike typical miscibility transitions in which compact domains may coexist at equilibrium, the LAT condensates are dynamically arrested in extended states, kinetically trapped out of equilibrium. Modeling identifies the structural basis for this kinetic arrest as the formation of spindle arrangements, favored by limited multivalent binding interactions along the flexible, intrinsically disordered LAT protein. These results reveal how local factors controlling the kinetics of LAT condensation enable formation of different, stable condensates, which may ultimately coexist within the cell. Published version This work was supported by the Novo Nordisk Foundation Challenge Program under the Center for Geometrically Engineered Cellular Systems. Additional support was provided by NIH grant PO1 A1091580. T.G. and D.T.L were supported by the NSF, Division of Chemistry award no. NSF grant CHE1954580. 2023-10-12T06:35:09Z 2023-10-12T06:35:09Z 2022 Journal Article Sun, S., GrandPre, T., Limmer, D. T. & Groves, J. T. (2022). Kinetic frustration by limited bond availability controls the LAT protein condensation phase transition on membranes. Science Advances, 8(44). https://dx.doi.org/10.1126/sciadv.abo5295 2375-2548 https://hdl.handle.net/10356/170826 10.1126/sciadv.abo5295 36322659 2-s2.0-85141214041 44 8 en Science Advances © 2022 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC). application/pdf |
| spellingShingle | Science::Chemistry Amino Acids Protein-Protein Interactions Sun, Simou GrandPre, Trevor Limmer, David T. Groves, Jay T. Kinetic frustration by limited bond availability controls the LAT protein condensation phase transition on membranes |
| title | Kinetic frustration by limited bond availability controls the LAT protein condensation phase transition on membranes |
| title_full | Kinetic frustration by limited bond availability controls the LAT protein condensation phase transition on membranes |
| title_fullStr | Kinetic frustration by limited bond availability controls the LAT protein condensation phase transition on membranes |
| title_full_unstemmed | Kinetic frustration by limited bond availability controls the LAT protein condensation phase transition on membranes |
| title_short | Kinetic frustration by limited bond availability controls the LAT protein condensation phase transition on membranes |
| title_sort | kinetic frustration by limited bond availability controls the lat protein condensation phase transition on membranes |
| topic | Science::Chemistry Amino Acids Protein-Protein Interactions |
| url | https://hdl.handle.net/10356/170826 |
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