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Receptor-mediated dimerization of JAK2 FERM domains is required for JAK2 activation.
Ferrao, Ryan D; Wallweber, Heidi Ja; Lupardus, Patrick J.
Afiliação
  • Ferrao RD; Department of Structural Biology, Genentech, Inc., South San Francisco, United States.
  • Wallweber HJ; Department of Structural Biology, Genentech, Inc., South San Francisco, United States.
  • Lupardus PJ; Department of Structural Biology, Genentech, Inc., South San Francisco, United States.
Elife ; 72018 07 25.
Article em En | MEDLINE | ID: mdl-30044226
Cytokines and interferons initiate intracellular signaling via receptor dimerization and activation of Janus kinases (JAKs). How JAKs structurally respond to changes in receptor conformation induced by ligand binding is not known. Here, we present two crystal structures of the human JAK2 FERM and SH2 domains bound to Leptin receptor (LEPR) and Erythropoietin receptor (EPOR), which identify a novel dimeric conformation for JAK2. This 2:2 JAK2/receptor dimer, observed in both structures, identifies a previously uncharacterized receptor interaction essential to dimer formation that is mediated by a membrane-proximal peptide motif called the 'switch' region. Mutation of the receptor switch region disrupts STAT phosphorylation but does not affect JAK2 binding, indicating that receptor-mediated formation of the JAK2 FERM dimer is required for kinase activation. These data uncover the structural and molecular basis for how a cytokine-bound active receptor dimer brings together two JAK2 molecules to stimulate JAK2 kinase activity.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Fragmentos de Peptídeos / Conformação Proteica / Receptores da Eritropoetina / Janus Quinase 2 / Receptores para Leptina Tipo de estudo: Prognostic_studies Limite: Humans Idioma: En Revista: Elife Ano de publicação: 2018 Tipo de documento: Article País de afiliação: Estados Unidos País de publicação: Reino Unido

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Fragmentos de Peptídeos / Conformação Proteica / Receptores da Eritropoetina / Janus Quinase 2 / Receptores para Leptina Tipo de estudo: Prognostic_studies Limite: Humans Idioma: En Revista: Elife Ano de publicação: 2018 Tipo de documento: Article País de afiliação: Estados Unidos País de publicação: Reino Unido