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. Author manuscript; available in PMC: 2024 May 15.
Published in final edited form as: J Immunol. 2023 Nov 15;211(10):1450–1458. doi: 10.4049/jimmunol.2200682

Figure 2. SNVs in TCR signaling pathway members disrupt key regulatory domains.

Figure 2.

The mutation locations within protein domains are shown in the lollipop diagrams (created with trackViewer(130)). The pie graph above a mutation position contains the percentage of the mutations within a gene that lie at the location for each TCL(26, 47, 69, 75, 131). They are ordered, from bottom to top, as AITL (red), ATL (yellow), CTCL (blue), and PTCL-NOS (purple). The autoinhibition mechanisms of TCR pathway members are shown in the structural diagrams. Point mutations affecting key domains are marked with a lightning bolt. Truncating mutations are marked with a stop figure. The left figures labeled “inhibited” show the interactions at basal state. The right figure labeled “activated” show the active conformation and the effects of mutations. A. Point mutations of FYN frequently occur in the SH3, SH2, and kinase domains. The most commonly mutated sites are p.R96 and p.R176. B. FYN is autoinhibited by the SH2 domain interacting with the C-terminus Y527 and SH3 domain interacting with the SH2-kinase linker domain. The Trp264 residue interacts with the αC helix of the kinase domain. During activation, the kinase domain is free to bind substrate. C-terminus mutations/truncations or mutations in the SH2 or SH3 domains disrupt the inhibitory interaction. C. Point mutations in PLCG1 frequently occur in the PH, catalytic, and C2 domains. The most commonly mutated sites are p.R48, p.S345, p.E1163, and p.D1165. D. The PLCG1 p.Y783 site is phosphorylated during activation and frees the catalytic core by binding to the C-SH2 domain. Mutations in the catalytic core or in the PH domain disrupt the autoinhibitory interface, allowing the catalytic core to access substrate. E. Point mutations in VAV1 frequently occur in the acidic linker region, PH, ZF, and C-SH3 domains. The most commonly mutated site is p.E556. F. VAV1 autoinhibition is mediated by Ac, PH, and CH domains that block the DH domain active site. Mutations in the Ac or DH domain disrupt the autoinhibition. Truncating or point mutations in the C-terminal SH3 domain are also frequently seen in TCLs. G. Point mutations in RHOA frequently occur in the GTP binding domains. The most commonly mutated site is p.G17. H. Point mutations in PRKCB frequently occur in the protein kinase domains. The most commonly mutated site is p.D427. I. PRKCB features a C1b domain that sequesters the essential p.F629 residue from the active site during autoinhibition. Mutations in the protein kinase N-lobe allow activation independent of upstream kinases. J. Point mutations in CARD11 frequently occur in the coiled coil and inhibitory domains. The most commonly mutated sites are p.D401 and p.E626. K. CARD11 forms an autoinhibited structure featuring multiple interactions with the inhibitory domain (ID). Phosphorylation of the domain activates CARD11. Mutations affecting the ID domain or linker region enables autonomous activation of CARD11.