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Laboratory of Structural Biology 2010. 10. 18 Kim Byeong -won

Laboratory of Structural Biology 2010. 10. 18 Kim Byeong -won. Tec family kinase. Tec family kinase Btk ( B ruton`s t yrosine k inase ) Itk ( I L-2 t yrosine k inase ) Bmx ( B one m arrow kinase on the X chromosome) Rlk ( R esting l ymphocyte k inase ) Function

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Laboratory of Structural Biology 2010. 10. 18 Kim Byeong -won

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  1. Laboratory of Structural Biology 2010. 10. 18 Kim Byeong-won

  2. Tec family kinase • Tec family kinase • Btk (Bruton`styrosine kinase) • Itk (IL-2 tyrosine kinase) • Bmx (Bone marrow kinase on the X chromosome) • Rlk (Resting lymphocyte kinase) • Function • Signaling pathways downstream of the antigen receptors • Primarily expressed in the hematopoietic system

  3. Itk • Domain • PH : pleckstrin homology • TH : Tec homology • SH : Src homology • Non-canonical interaction • SH2 domain binds to kinase domain but doesn`t involve the phosphopeptide (=ligand) binding pocket of the SH2 domain

  4. Results • Results • Mutations in the Itk SH2 domain docking site disrupt autophosphorylation • The substrate-docking surface is distinct from the canonical Itk SH2 domain ligand-binding surface • The Btk SH2 domain XLA(X-linked agammaglobulinemia) mutations affect SH2-mediated substrate docking • Structural model of Itk during autophosphorylation

  5. The SH2 domain of each Tec kinase docks onto the kinase domain • 4,7 and 10 : SH3-SH2 domain of Itk • 5,8, and 11 : SH3-SH2 domain of Btk • 6. 9 and 12 : SH3-SH2 domain of Tec Full-length

  6. Mapping of the Itk SH2 domain substrate-docking surface

  7. Mutations in the Itk SH2 domain disrupt phosphorylation on Y180

  8. Mutations in the Itk SH2 domain disrupt phosphorylation on Y180

  9. The Itk SH2 domain substrate-docking surface

  10. The Itk SH2 domain substrate-docking surface Ligand interaction with R265

  11. Mutations in the docking site disrupt autophosphorylation in Itk • The Lckkinasephosphorylate Y511 in Itk activation loop by activating Itk

  12. Mutations in the SH2 domain docking site disrupt autophosphorylation in Itk

  13. The Btk SH2 domain affect SH2-mediated substrate docking Btk SH3 domain

  14. Structural model of Itk during autophosphorylation Ligand-binding pocket

  15. Summary • It is evident that there are various signal transduction pathways that are mediated by non-phosphotyrosine-dependent SH2 interaction. • The SH2 domain can mediate Y180 phosphorylation while retaining binding to at least the phosphotyrosine of a phospholigand in the signaling complex. • While the observed connection between the BtkXla-causing mutations and disruption of substrate docking is compelling, futher experiments are clearly needed to confirm a link between a protein interaction interface and disease.

  16. Thank you

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