Interaction between Btk TH and SH3 domain

Okoh, Michael P.; Vihinen, Mauno

doi:10.1002/bip.10049

Cited by 16 publications

(11 citation statements)

References 62 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In c-Src and Hck, the SH2 domain interacts with a C-terminal tyrosine residue and the SH3 domain binds to the linker between the SH2 and kinase domains, resulting in inactive conformation of the activation loop and blockage of the substrate-binding site Xu et al, 1997Xu et al, , 1999. In Tec family kinases Itk and Btk, the SH3 domain interacts with the adjacent proline-rich region (Andreotti et al, 1997;Hansson et al, 2001;Okoh and Vihinen, 2002). In c-Abl, the N-terminal region is responsible for the inhibition of the kinase domain through intramolecular interaction (Pluk et al, 2002).…”

Section: Discussionmentioning

confidence: 99%

Autoinhibition of Jak2 Tyrosine Kinase Is Dependent on Specific Regions in Its Pseudokinase Domain

Saharinen

Vihinen

Silvennoinen³

2003

MBoC

Self Cite

198

142

View full text Add to dashboard Cite

Jak tyrosine kinases have a unique domain structure containing a kinase domain (JH1) adjacent to a catalytically inactive pseudokinase domain (JH2). JH2 is crucial for inhibition of basal Jak activity, but the mechanism of this regulation has remained elusive. We show that JH2 negatively regulated Jak2 in bacterial cells, indicating that regulation is an intrinsic property of Jak2. JH2 suppressed basal Jak2 activity by lowering the V max of Jak2, whereas JH2 did not affect the K m of Jak2 for a peptide substrate. Three inhibitory regions (IR1-3) within JH2 were identified. IR3 (residues 758 -807), at the C terminus of JH2, directly inhibited JH1, suggesting an inhibitory interaction between IR3 and JH1. Molecular modeling of JH2 showed that IR3 could form a stable ␣-helical fold, supporting that IR3 could independently inhibit JH1. IR2 (725-757) in the Cterminal lobe of JH2, and IR1 (619 -670), extending from the N-terminal to the C-terminal lobe, enhanced IR3-mediated inhibition of JH1. Disruption of IR3 either by mutations or a small deletion increased basal Jak2 activity, but abolished interferon-␥-inducible signaling. Together, the results provide evidence for autoinhibition of a Jak family kinase and identify JH2 regions important for autoregulation of Jak2.

show abstract

Section: Discussionmentioning

confidence: 99%

Autoinhibition of Jak2 Tyrosine Kinase Is Dependent on Specific Regions in Its Pseudokinase Domain

Saharinen

Vihinen

Silvennoinen³

2003

MBoC

Self Cite

198

142

View full text Add to dashboard Cite

show abstract

“…Structural studies using different Tec kinase fragments indicate that the noncatalytic regulatory domains interact in an intermolecular fashion driving multimerization in solution (Andreotti et al 1997;Brazin et al 2000;Hansson et al 2001;Laederach et al 2002;Okoh and Vihinen 2002;Pursglove et al 2002;Laederach et al 2003;Severin et al 2009). For Itk, multimerization is mediated by self-association of the PH domain (Huang et al 2007) and intermolecular interactions between the SH3 and SH2 domains of different Itk molecules (Brazin et al 2000;Severin et al 2009).…”

Section: Regulation Of Itk Activity By Multimerizationmentioning

confidence: 99%

T-Cell Signaling Regulated by the Tec Family Kinase, Itk

Andreotti¹,

Schwartzberg²,

Joseph³

et al. 2010

Cold Spring Harbor Perspectives in Biology

209

228

View full text Add to dashboard Cite

The Tec family tyrosine kinases regulate lymphocyte development, activation, and differentiation. In T cells, the predominant Tec kinase is Itk, which functions downstream of the T-cell receptor to regulate phospholipase C-g. This review highlights recent advances in our understanding of Itk kinase structure and enzymatic regulation, focusing on Itk protein domain interactions and mechanisms of substrate recognition. We also discuss the role of Itk in the development of conventional versus innate T-cell lineages, including both ab and gd T-cell subsets. Finally, we describe the complex role of Itk signaling in effector T-cell differentiation and the regulation of cytokine gene expression. Together, these data implicate Itk as an important modulator of T-cell signaling and function.

show abstract

“…TH region is important for the autoregulation of Tec-kinases, which can further be divided into a Zn 2+ binding region called BTK motif (BM) and a proline-rich region [20,21]. The SH2 can bind to sequences containing phosphorylated tyrosine residues [22,23], and SH3 can interact with other proline-rich sequences [24][25][26]. Y551 in the SH1 domain is phosphorylated by Src-kinases Lyn and/or Syk.…”

Section: Discussionmentioning

confidence: 99%