The IFNG receptor complex is a pre-assembled entity, as constitutive interactions are seen between IFNGR1 and IFNGR2, and between two IFNGR2 chains in the absence of ligand IFNG. JAK1 and JAK2 constitutively associate with the intracellular domains of the subunits of the IFNG receptor complex, providing it with tyrosine kinase activity. In unstimulated cells JAK1 preferentially associates with IFNGR1 and while JAK2 associates with IFNGR2 chains. JAK1 enhances the interaction between IFNGR1 and IFNGR2 chains, and thus has a major role in the pre-assembly of the IFNGR complex, in contrast the kinase activity of JAK2 is required to observe any signaling by IFNG.
IFNG binds directly to both the receptor chains IFNGR1 and IFNGR2. IFNGR1 is a high affinity receptor and binds directly to IFNG whereas IFNGR2 binds to IFNG in presence of IFNGR1. According to Krause et al. model IFNG binds to IFNGR1 chains first and then IFNGR2 chains interact with the IFNGR1:IFNG:IFNGR1 complex.