Laboratory of structural biology 2010 10 18 kim byeong won
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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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Laboratory of Structural Biology

2010. 10. 18

Kim Byeong-won


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


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


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


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


Mapping of the Itk SH2 domain substrate-docking surface


Mutations in the Itk SH2 domain disrupt phosphorylation on Y180


Mutations in the Itk SH2 domain disrupt phosphorylation on Y180


The Itk SH2 domain substrate-docking surface


The Itk SH2 domain substrate-docking surface

Ligand interaction with R265


Mutations in the docking site disrupt autophosphorylation in Itk

  • The Lckkinasephosphorylate Y511 in Itk activation loop by activating Itk


Mutations in the SH2 domain docking site disrupt autophosphorylation in Itk


The Btk SH2 domain affect SH2-mediated substrate docking

Btk SH3 domain


Structural model of Itk during autophosphorylation

Ligand-binding pocket


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.


Thank you


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