Association of the EF-hand and PH domains of the guanine nucleotide exchange factor SLAT with IP3 receptor 1 promotes Ca2+ signaling in T cells

The guanine nucleotide exchange factor SLAT (SWAP-70–like adaptor of T cells) regulates T cell activation and differentiation by enabling Ca 2+ release from intracellular stores in response to stimulation of the T cell receptor (TCR). We found a TCR-induced association between SLAT and inositol 1,4,5-trisphosphate (IP 3 ) receptor type 1 (IP 3 R1). The N-terminal region of SLAT, which contains two EF-hand motifs that we determined bound Ca 2+ , and the SLAT pleckstrin homology (PH) domain independently bound to IP 3 R1 by associating with a conserved motif within the IP 3 R1 ligand-binding domain. Disruption of the SLAT-IP 3 R1 interaction with cell-permeable, IP 3 R1-based fusion peptides inhibited TCR-stimulated Ca 2+ signaling, activation of the transcription factor NFAT (nuclear factor of activated T cells), and production of cytokines, suggesting that this interaction is required for optimal T cell activation. The finding that SLAT is an IP 3 R1-interacting protein required for T cell activation suggests that this interaction could be a potential target for a selective immunosuppressive drug.