Details

Autor(en) / Beteiligte

• Lanz, Anna-Lisa
• Masi, Giulia
• Porciello, Nicla
• Cohnen, André
• Cipria, Deborah
• Prakaash, Dheeraj
• Bálint, Štefan
• Raggiaschi, Roberto
• Galgano, Donatella
• Cole, David K.
• Lepore, Marco
• Dushek, Omer
• Dustin, Michael L.
• Sansom, Mark S.P.
• Kalli, Antreas C.
• Acuto, Oreste

Titel

Allosteric activation of T cell antigen receptor signaling by quaternary structure relaxation

Ist Teil von

• Cell reports (Cambridge), 2021-07, Vol.36 (2), p.109375-109375, Article 109375

Ort / Verlag

United States: Elsevier Inc

Erscheinungsjahr

2021

Quelle

Free E-Journal (出版社公開部分のみ）

Beschreibungen/Notizen

• The mechanism of T cell antigen receptor (TCR-CD3) signaling remains elusive. Here, we identify mutations in the transmembrane region of TCRβ or CD3ζ that augment peptide-major histocompatibility complex (pMHC)-induced signaling not explicable by enhanced ligand binding, lateral diffusion, clustering, or co-receptor function. Using a biochemical assay and molecular dynamics simulation, we demonstrate that the gain-of-function mutations loosen the interaction between TCRαβ and CD3ζ. Similar to the activating mutations, pMHC binding reduces TCRαβ cohesion with CD3ζ. This event occurs prior to CD3ζ phosphorylation and at 0°C. Moreover, we demonstrate that soluble monovalent pMHC alone induces signaling and reduces TCRαβ cohesion with CD3ζ in membrane-bound or solubilised TCR-CD3. Our data provide compelling evidence that pMHC binding suffices to activate allosteric changes propagating from TCRαβ to the CD3 subunits, reconfiguring interchain transmembrane region interactions. These dynamic modifications could change the arrangement of TCR-CD3 boundary lipids to license CD3ζ phosphorylation and initiate signal propagation. [Display omitted] •Mutations in TCRβ and CD3ζ TMRs that reduce their interaction augment signaling•pMHC and anti-CD3 binding to TCR-CD3 induce similar quaternary structure relaxation•Soluble monovalent pMHC alone signals and reduces TCRαβ cohesion with CD3ζ•Allosteric changes in TCR-CD3 dynamics instigate T cell activation T cell antigen receptor is central in adaptive immunity; however, the mechanism that couples ligand binding and intracellular signaling is still controversial. Here, Lanz et al. have taken an interdisciplinary approach demonstrating that binding of soluble monovalent pMHC to TCR-CD3 allosterically reduces TCRαβ cohesion with CD3ζ and initiates signal transduction.