Positive feedback between the T cell kinase Zap70 and its substrate LAT acts as a clustering-dependent signaling switch.

TitlePositive feedback between the T cell kinase Zap70 and its substrate LAT acts as a clustering-dependent signaling switch.
Publication TypeJournal Article
Year of Publication2021
AuthorsDine, E, Reed, EH, Toettcher, JE
JournalCell Rep
Volume35
Issue12
Pagination109280
Date Published2021 Jun 22
ISSN2211-1247
Abstract

<p>Protein clustering is pervasive in cell signaling, yet how signaling from higher-order assemblies differs from simpler forms of molecular organization is still poorly understood. We present an optogenetic approach to switch between oligomers and heterodimers with a single point mutation. We apply this system to study signaling from the kinase Zap70 and its substrate linker for activation of T cells (LAT), proteins that normally form membrane-localized condensates during T cell activation. We find that fibroblasts expressing synthetic Zap70:LAT clusters activate downstream signaling, whereas one-to-one heterodimers do not. We provide evidence that clusters harbor a positive feedback loop among Zap70, LAT, and Src-family kinases that binds phosphorylated LAT and further activates Zap70. Finally, we extend our optogenetic approach to the native T cell signaling context, where light-induced LAT clustering is sufficient to drive a calcium response. Our study reveals a specific signaling function for protein clusters and identifies a biochemical circuit that robustly senses protein oligomerization state.</p>

DOI10.1016/j.celrep.2021.109280
Alternate JournalCell Rep
PubMed ID34161759
PubMed Central IDPMC8292983
Grant ListDP2 EB024247 / EB / NIBIB NIH HHS / United States
F31 AI145218 / AI / NIAID NIH HHS / United States
T32 GM007388 / GM / NIGMS NIH HHS / United States