Type II cytokine receptor

Type II cytokine receptors are related predominantly by sequence similarities in their extracellular portions that are composed of tandem Ig-like (FN3) domains. The structures for the extracellular domains of the receptors for interferon types, I, II, and III are all known.^[6] Type II cytokine receptors are tyrosine-kinase-linked receptors. The intracellular domain of type II cytokine receptors is typically associated with a tyrosine kinase belonging to the Janus kinase (JAK family). Binding of the receptor typically leads to activation of the canonical JAK/STAT signaling pathway.^[7]

Like other cytokine receptors, many type II CRs are heterodimers or multimers with a high and a low affinity component. The high-affinity component is cytokine‐specific and, again like other CRs, is often the α chain. The low-affinity component remains required for forming a functional complex: in some examples such as IFN III, the ligand first binds to the α chain, then the two molecules together recruits a "shared" β chain.^[8]

Typical CRFBs have an alpha chain and a beta chain. Each chain contains two (except for IFNAR1) N-terminal extracellular ligand-binding fibronectin type III domains (FN3; each pair is called a cytokine homology region, CHR), then extends intracellularly. Unlike class I CRs, all chains (even alpha) bind a kinase to participate in signaling. The shorter one (<100 intracellular residues, usually α) typically binds either JAK2 or TYK2, and the longer one typically interacts with JAK1. Interaction with JAK1 is mediated by a conserved motif PxxLxF (box1). There is a neighboring box2 that by itself poorly binds JAK1, but improves the binding between box1 and JAK1 in vitro. C-terminal to the two kinase boxes, mainly on the "long" chain, is a disordered region that binds STAT.^[9] TYK2 binding is greatly dependent on box2.^[8]

There are many variations on the theme among the type II receptors, including a high-affinity β chain, some non-shared chains, and doubled stoichiometry where the complex is a heterotetramer assembled on binding a heterodimer cytokine (IFN II and IL-10 family members).^[8]

Type II cytokine receptors include those that bind interferons and those that bind members of the interleukin-10 family (interleukin-10, interleukin-20, interleukin-22, and interleukin-28).^[3][2] Expression of specific receptor varieties is highly variable across tissue types with some receptors being ubiquitously expressed and some receptors only expressed in specific tissues.^[4]