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Structural basis of recognition of interferon-? receptor by tyrosine kinase 2.

ABSTRACT: 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-? 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.

SUBMITTER: Wallweber HJ

PROVIDER: S-EPMC4161281 | biostudies-literature | 2014 May

REPOSITORIES: biostudies-literature

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

Wallweber Heidi J A HJ Tam Christine C Franke Yvonne Y Starovasnik Melissa A MA Lupardus Patrick J PJ

Nature structural & molecular biology 20140406 5

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-b ...[more]

PMID: 24704786

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