Figure 2. Structural basis of SYK activation.

a ∣ Three different states of SYK activation. SYK is autoinhibited in its resting state, due to the binding of interdomain A (“A”) and interdomain B (“B”) to the kinase domain, in particular, the C-terminal end. This autoinhibited conformation can be suspended by binding of the two SH2 domains to dually phosphorylated ITAMs or by phosphorylation of linker tyrosines in interdomain A or B. There is a logic “OR” relationship between those two activation mechanisms. b ∣ The domain structure of SYK with tyrosine residues shown to be sites of autophosphorylation. Proteins shown to bind to phosphorylated tyrosines are indicated above the tyrosine residues. p85α, the 85 kDa PI3K regulatory subunit. c ∣ Combined mechanism of SYK activation. Prior to activation, SYK is held in an autoinhibited conformation by interactions between interdomains A and B and the kinase domain. Initial phosphorylation of ITAM tyrosines by SRC-family kinases provides docking sites for the SYK SH2 domains inducing conformational changes and kinase activation. SYK activation results in autophoshorylation on multiple residues, leading to release from the ITAM and sustained SYK activation. SYK then recruits direct binding partners to its phosphorylated tyrosine residues, triggering downstream signaling. Phosphorylation of ITAM tyrosine by SYK provides a positive feedback loop. Amino acid numbers correspond to the sequence of mouse SYK. Phosphorylation of the linker tyrosines are highlighted in orange colour.