Campus Units

Biochemistry, Biophysics and Molecular Biology

Document Type

Article

Publication Version

Accepted Manuscript

Publication Date

8-7-2009

Journal or Book Title

Journal of Molecular Biology

Volume

391

Issue

1

First Page

164

Last Page

177

DOI

10.1016/j.jmb.2009.06.023

Abstract

The Tec family kinase, Itk (interleukin-2 tyrosine kinase), undergoes an in cis autophosphorylation on Y180 within its Src homology 3 (SH3) domain. Autophosphorylation of the Itk SH3 domain by the Itk kinase domain is strictly dependent on the presence of the intervening Src homology 2 (SH2) domain. A direct docking interaction between the Itk kinase and SH2 domains brings the Itk SH3 domain into the active site where Y180 is then phosphorylated. We now identify the residues on the surface of the Itk SH2 domain responsible for substrate docking and show that this SH2 surface mediates autophosphorylation in the full-length Itk molecule. The canonical phospholigand binding site on the SH2 domain is not involved in substrate docking, instead the docking site consists of side chains from three loop regions (AB, EF and BG) and part of the βD strand. These results are extended into Btk (Bruton's tyrosine kinase), a Tec family kinase linked to the B-cell deficiency X-linked agammaglobulinemia (XLA). Our results suggest that some XLA-causing mutations might impair Btk phosphorylation.

Comments

This article is from Journal of Molecular Biology 391 (2009): 164–177, doi:10.1016/j.jmb.2009.06.023. Posted with permission.

Copyright Owner

Elsevier Ltd.

Language

en

File Format

application/pdf

Published Version

Share

COinS