Intrinsic Disorder in the T Cell Receptor Creates Cooperativity and Controls ZAP70 Binding

Abstract

Many immunoreceptors have cytoplasmic domains that are intrinsically disordered (i.e., have high configurational entropy), have multiple sites of posttranslational modification (e.g., tyrosine phosphorylation), and participate in nonlinear signaling pathways (e.g., exhibiting switch-like behavior). Several hypotheses to explain the origin of these nonlinearities fall under the broad hypothesis that modification at one site changes the immunoreceptor’s entropy, which in turn changes further modification dynamics. Here, we use coarse-grain simulation to study three scenarios, all related to the chains that constitute the T cell receptor (TCR). We find that first, if phosphorylation induces local changes in the flexibility of the TCR ζ -chain, this naturally leads to rate enhancements and cooperativity. Second, we find that TCR CD3 ɛ can provide a switch by modulating its residence in the plasma membrane. By constraining our model to be consistent with the previous observation that both basic residues and phosphorylation control membrane residence, we find that there is only a moderate rate enhancement of 10% between first and subsequent phosphorylation events. Third, we find that volume constraints do not limit the number of ZAP70s that can bind the TCR but that entropic penalties lead to a 200-fold decrease in binding rate by the seventh ZAP70, potentially explaining the observation that each TCR has around six ZAP70 molecules bound after receptor triggering. In all three scenarios, our results demonstrate that phenomena that change an immunoreceptor chain’s entropy (stiffening, confinement to a membrane, and multiple simultaneous binding) can lead to nonlinearities (rate enhancement, switching, and negative cooperativity) in how the receptor participates in signaling. These polymer-entropy-driven nonlinearities may augment the nonlinearities that arise from, e.g., kinetic proofreading and cluster formation. They also suggest different design strategies for engineered receptors, e.g., whether or not to put signaling modules on one chain or multiple clustered chains.

An evolutionary divergent thermodynamic brake in ZAP-70 fine-tunes the kinetic proofreading in T cells

“…The ‘open to closed’ structural transitions of ZAP-70 tSH2 domain upon ligand binding requires cooperative interaction between the ITAM peptide, and the allosteric network resides in the tSH2 domain ( Fig. 1 C ) ( 17 , 33 , 45 ). Analyzing the crystal structure of ZAP-70 tSH2 domain in complex with ITAM-Y2P-ζ1 ( 19 ), we identified a salt-bridge between the ITAM-ζ1 E13 and tSH2 K245 residue that may be critical for the structural coupling between the N- and C-SH2 domain during ligand binding ( Fig.…”

A teamwork promotion of formin-mediated actin nucleation by Bud6 and Aip5 in Saccharomyces cerevisiae

“…IDRs have highly variable binding affinities for diverse modes of molecular interactions and exhibit a broad range of binding modes with biomolecules depending on the length and amino acid composition, which results in nonlinearities in inter- and intramolecular interactions ( Li et al. , 2020 ; Clemens et al. , 2021 ).…”

Regulating the discriminatory response to antigen by T-cell receptor

“…[ 50–55 ]. The phosphorylated CD3 chains serve as a docking site for the second non-receptor tyrosine kinase named zeta chain-associated protein tyrosine kinase (ZAP-70) [ 56–59 ]. The discriminative ability of TCR relies on two different events, the affinity of the antigenic peptide for the extracellular receptor [ 60 ] and the intracellular balance between downstream kinases and phosphatases, creating a feedback regulation [ 61–65 ].…”