Fig. 4.

Activation of the TEC kinases. T-cell or B-cell stimulation generates ligands for the regulatory domains of the TEC kinases which promote the formation of signaling complexes that nucleate around non-catalytic scaffolding proteins such as SLP-76 in T-cells (or SLP-65 in B cells). These interactions with the regulatory domains disrupt the ‘closed’ autoinhibited conformation of TEC kinases to a more ‘open’ form (a). Crystal structures reveal dimerization (b, left) of the BTK N-terminal PHTH domain bound to the PIP₃ headgroup, IP₄, now known as the ‘Saraste dimer’. Subsequent structures of the BTK PHTH dimer (Wang et al., 2015) revealed additional phospholipid binding sites; the canonical site (circled) as well as a peripheral site (boxed) on each domain in the dimer (b, right). Elegant studies using fluorescence correlation spectroscopy and membrane-binding kinetic measurements revealed a role for the peripheral site in setting a PIP₃ threshold required to trigger BTK activation (Chung et al., 2019). (c) Interactions between the PXXP motif (red) in adaptor proteins and the SH3 domains of ITK/BTK (Bunnell et al., 2000) contribute to the unraveling of the compact autoinhibitory pose by displacing the SH2-kinase linker (grey). (d) Phosphotyrosine binding (SLP-76 pY145 is shown in (a)) to the ITK/BTK SH2 domain is sterically incompatible with the autoinhibitory interaction between the SH2 and the C-terminal region of the kinase domain (shown in Fig. 2a,iii) leading to displacement of the intramolecular SH2 inhibitory interaction and a shift toward the active conformation. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)