Disordered protein LAT encodes relative levels of signaling pathways in T cell activation

• 成果类型: Article
• 署名作者: Rubin, Adam J.; Dao, Tyler T.; Schueppert, Amelia V.; Choi, Saehyun; Groves, Jay T.; Regev, Aviv; Shalek, Alex K.
• 署名单位: Harvard University; Massachusetts Institute of Technology (MIT); Broad Institute; Massachusetts Institute of Technology (MIT); Harvard University; Massachusetts Institute of Technology (MIT); Harvard Medical School; Ragon Institute; Harvard University Medical Affiliates; Massachusetts General Hospital; Massachusetts Institute of Technology (MIT); University of California System; University of California Berkeley; Massachusetts Institute of Technology (MIT)
• 刊物名称: SCIENCE
• ISSN/ISSBN: 0036-8075; 1095-9203
• DOI: 10.1126/science.ads6847
• 发表日期: 2026-04-30
• 页码: eads6847
• 关键词: single-cell; TYROSINE RESIDUES; LINKER; seq; receptor; GRB2; mechanisms; mutations; selection; screens

摘要

The disordered adapter protein linker for activation of T cells (LAT) propagates T cell receptor signaling. To interrogate how LAT coordinates multiple downstream pathways, we developed a single-cell screening approach, identifying widespread functional segments including protein interaction motifs and blocks of negative charge. Regardless of their position in LAT, individual segments generally conferred defects across all downstream signaling pathways. To understand the underlying mechanism, we used molecular biology, computational modeling, and imaging to demonstrate that disruption of LAT interaction with a single partner protein indirectly disrupts other partner interactions, likely through the dual roles of these proteins as effectors of downstream signaling and bridging factors between LAT molecules. Overall, we describe an extendable approach for interrogating sequence-function relationships for proteins with complex activities.