<p>Following TCR-pMHC binding, Itk molecules are bound by the LAT signalosome via SLP-76 (not shown). Itk molecules (monomers or dimers, blue diamonds), bind the membrane lipid PIP<sub>3</sub> with low affinity through their PH domains. PIP<sub>3</sub> bound Itk phosphorylates and thereby activates LAT-bound PLCγ1. Activated PLCγ1 then hydrolyzes the membrane lipid PIP<sub>2</sub> into the soluble second messenger IP<sub>3</sub>, a key mediator of Ca<sup>2+</sup> mobilization. IP<sub>3</sub> 3-kinase B (ItpkB) converts IP<sub>3</sub> into IP<sub>4</sub> (red filled circle). For our <i>in silico</i> models, we simplified this series of reactions, encircled by the orange oval, into a single second order reaction where PIP<sub>3</sub> bound Itk converts PIP<sub>2</sub> into IP<sub>4</sub>. In models M1–M4 and M7, IP<sub>4</sub> modifies the Itk PH domain (denoted as Itk<sup>C</sup>, purple diamonds) to promote PIP<sub>3</sub> and IP<sub>4</sub> binding to the Itk PH domain. At the onset of the signaling, when the concentration of IP<sub>4</sub> is smaller than that of PIP<sub>3</sub>, IP<sub>4</sub> helps Itk<sup>C</sup> to bind to PIP<sub>3</sub> (left lower panel). However, as the concentration of IP<sub>4</sub> is increased at later times, IP<sub>4</sub> outcompetes PIP<sub>3</sub> for binding to Itk<sup>C</sup> and sequesters Itk<sup>C</sup> to the cytosol (right lower panel). In models M5/M6, IP<sub>4</sub> and PIP<sub>3</sub> do not augment each other’s binding to Itk. However, IP<sub>4</sub> still outcompetes PIP<sub>3</sub> for Itk PH domain binding when the number of IP<sub>4</sub> molecules becomes much larger than that of PIP<sub>3</sub> molecules at later times.</p

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