Structural basis of recognition of interferon-α receptor by tyrosine kinase 2.
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.
Department of Structural Biology, Genentech, South San Francisco, California, USA.
Heidi J A
HJ
Wallweber
Department of Structural Biology, Genentech, South San Francisco, California, USA.
Christine
C
Tam
Department of Structural Biology, Genentech, South San Francisco, California, USA.
Yvonne
Y
Franke
Department of Structural Biology, Genentech, South San Francisco, California, USA.
Melissa A
MA
Starovasnik
Department of Structural Biology, Genentech, South San Francisco, California, USA.
Patrick J
PJ
Lupardus
D000595:Amino Acid Sequence; D001665:Binding Sites; D017124:Conserved Sequence; D018360:Crystallography, X-Ray; D006801:Humans; D016898:Interferon-alpha / Q000737:chemistry* / Q000378:metabolism; D008958:Models, Molecular; D008969:Molecular Sequence Data; D017434:Protein Structure, Tertiary; D053634:TYK2 Kinase / Q000737:chemistry* / Q000378:metabolism
D016898:Interferon-alpha; D053634:TYK2 Kinase