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

Laboratory of Structural Biology

2010. 10. 18

Kim Byeong-won


Tec family kinase

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


Laboratory of structural biology 2010 10 18 kim byeong won

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

  • 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

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

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


Mutations in the itk sh2 domain disrupt phosphorylation on y1801

Mutations in the Itk SH2 domain disrupt phosphorylation on Y180


The itk sh2 domain substrate docking surface

The Itk SH2 domain substrate-docking surface


The itk sh2 domain substrate docking surface1

The Itk SH2 domain substrate-docking surface

Ligand interaction with R265


Mutations in the docking site disrupt autophosphorylation in itk

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

Mutations in the SH2 domain docking site disrupt autophosphorylation in Itk


The btk sh2 domain affect sh2 mediated substrate docking

The Btk SH2 domain affect SH2-mediated substrate docking

Btk SH3 domain


Structural model of itk during autophosphorylation

Structural model of Itk during autophosphorylation

Ligand-binding pocket


Summary

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

Thank you


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