The human interferon-gamma receptor complex consists the heterodimer of two chains: IFNGR1 and IFNGR2. In unstimulated cells, these subunits are not preassociated with each other but rather associate through their intracellular domains with inactive forms of specific Janus family kinases ( Jak1 and Jak2). Jak1 and Jak2 constitutively associate with IFNGR1 and IFNGR2, respectively. Binding of IFN-γ to IFNGR1 induces the rapid dimerization of IFNGR1 chains, thereby forming a site that is recognized by the extracellular domain of IFNGR2. The ligand-induced assembly of the complete receptor complex contains two IFNGR1 and two IFNGR2 subunits which bring into close juxtaposition the intracellular domains of these proteins together with the inactive Jak1 and Jak2 kinases that they associate with. In this complex, Jak1 and Jak2 transactivate one another and then phosphorylate IFNGR1, thereby forming a paired set of Stat1 docking sites on the ligated receptor. Two Stat1 molecules then associate with the paired docking sites, are brought into close proximity with receptor-associated activated JAK kinases, and are activated by phosphorylation of the Stat1. Tyrosine-phosphorylated Stat1 molecules dissociate from their receptor tether and form homodimeric complexes. Activated Stat1 translocates to the nucleus and, after binding to a specific sequence in the promoter region of immediate-early IFN-γ-inducible genes, effects gene transcription.
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