Structural basis of recognition of interferon-α receptor by tyrosine kinase 2

Nat Struct Mol Biol. 2014 May;21(5):443-8. doi: 10.1038/nsmb.2807. Epub 2014 Apr 6.


Tyrosine kinase 2 (TYK2) is a member of the Janus kinase (JAK) family of nonreceptor tyrosine kinases, which are essential for proper signaling in immune responses and development. Here we present a 2.0-Å-resolution crystal structure of a receptor-binding fragment of human TYK2, encompassing the FERM and SH2 domains, in complex with a so-called 'box2'-containing intracellular peptide motif from the interferon-α receptor chain 1 (IFNAR1). The TYK2-IFNAR1 interface reveals an unexpected receptor-binding mode that mimics a SH2 domain-phosphopeptide interaction, with a glutamate replacing the canonical phosphotyrosine residue. This structure provides the first view, to our knowledge, of a JAK in complex with its cognate receptor and defines the molecular logic through which JAKs have evolved to interact with divergent receptor sequences.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Amino Acid Sequence
  • Binding Sites
  • Conserved Sequence
  • Crystallography, X-Ray
  • Humans
  • Interferon-alpha / chemistry*
  • Interferon-alpha / metabolism
  • Models, Molecular
  • Molecular Sequence Data
  • Protein Structure, Tertiary
  • TYK2 Kinase / chemistry*
  • TYK2 Kinase / metabolism


  • Interferon-alpha
  • TYK2 Kinase

Associated data

  • PDB/4PO6