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Autoinhibition of Bruton's tyrosine kinase (Btk) and activation by soluble inositol hexakisphosphate.

Wang Q, Vogan EM, Nocka LM, Rosen CE, Zorn JA, Harrison SC, Kuriyan J - Elife (2015)

Bottom Line: In addition to the expected activation of Btk by membranes containing phosphatidylinositol triphosphate (PIP3), we found that inositol hexakisphosphate (IP6), a soluble signaling molecule found in both animal and plant cells, also activates Btk.This activation is a consequence of a transient PH-TH dimerization induced by IP6, which promotes transphosphorylation of the kinase domains.Sequence comparisons with other Tec-family kinases suggest that activation by IP6 is unique to Btk.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular and Cell Biology, Howard Hughes Medical Institute, University of California, Berkeley, Berkeley, United States.

ABSTRACT
Bruton's tyrosine kinase (Btk), a Tec-family tyrosine kinase, is essential for B-cell function. We present crystallographic and biochemical analyses of Btk, which together reveal molecular details of its autoinhibition and activation. Autoinhibited Btk adopts a compact conformation like that of inactive c-Src and c-Abl. A lipid-binding PH-TH module, unique to Tec kinases, acts in conjunction with the SH2 and SH3 domains to stabilize the inactive conformation. In addition to the expected activation of Btk by membranes containing phosphatidylinositol triphosphate (PIP3), we found that inositol hexakisphosphate (IP6), a soluble signaling molecule found in both animal and plant cells, also activates Btk. This activation is a consequence of a transient PH-TH dimerization induced by IP6, which promotes transphosphorylation of the kinase domains. Sequence comparisons with other Tec-family kinases suggest that activation by IP6 is unique to Btk.

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Sequence alignment of Btk and Itk.The alignment was performed using ClustalW2 (Larkin et al., 2007) and visualized by Espript3 (Robert and Gouet, 2014). The alignment shows that the adoption of the compact autoinhibited conformation by the Src-like module, seen in our crystal structures, is likely to be conserved in Itk. In contrast, residues at the Saraste dimer interface and at the peripheral IP6 binding site in Btk are not conserved in Itk.DOI:http://dx.doi.org/10.7554/eLife.06074.024
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fig10s1: Sequence alignment of Btk and Itk.The alignment was performed using ClustalW2 (Larkin et al., 2007) and visualized by Espript3 (Robert and Gouet, 2014). The alignment shows that the adoption of the compact autoinhibited conformation by the Src-like module, seen in our crystal structures, is likely to be conserved in Itk. In contrast, residues at the Saraste dimer interface and at the peripheral IP6 binding site in Btk are not conserved in Itk.DOI:http://dx.doi.org/10.7554/eLife.06074.024

Mentions: The Src-like modules of Btk and Itk have 55% sequence identity, with all the residues critical for maintaining the assembled and autoinhibited Src-like conformation of Btk conserved in Itk (Figure 10—figure supplement 1). The Src-like module of Itk is therefore likely also to adopt the assembled Src-like conformation when inactive.


Autoinhibition of Bruton's tyrosine kinase (Btk) and activation by soluble inositol hexakisphosphate.

Wang Q, Vogan EM, Nocka LM, Rosen CE, Zorn JA, Harrison SC, Kuriyan J - Elife (2015)

Sequence alignment of Btk and Itk.The alignment was performed using ClustalW2 (Larkin et al., 2007) and visualized by Espript3 (Robert and Gouet, 2014). The alignment shows that the adoption of the compact autoinhibited conformation by the Src-like module, seen in our crystal structures, is likely to be conserved in Itk. In contrast, residues at the Saraste dimer interface and at the peripheral IP6 binding site in Btk are not conserved in Itk.DOI:http://dx.doi.org/10.7554/eLife.06074.024
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4384635&req=5

fig10s1: Sequence alignment of Btk and Itk.The alignment was performed using ClustalW2 (Larkin et al., 2007) and visualized by Espript3 (Robert and Gouet, 2014). The alignment shows that the adoption of the compact autoinhibited conformation by the Src-like module, seen in our crystal structures, is likely to be conserved in Itk. In contrast, residues at the Saraste dimer interface and at the peripheral IP6 binding site in Btk are not conserved in Itk.DOI:http://dx.doi.org/10.7554/eLife.06074.024
Mentions: The Src-like modules of Btk and Itk have 55% sequence identity, with all the residues critical for maintaining the assembled and autoinhibited Src-like conformation of Btk conserved in Itk (Figure 10—figure supplement 1). The Src-like module of Itk is therefore likely also to adopt the assembled Src-like conformation when inactive.

Bottom Line: In addition to the expected activation of Btk by membranes containing phosphatidylinositol triphosphate (PIP3), we found that inositol hexakisphosphate (IP6), a soluble signaling molecule found in both animal and plant cells, also activates Btk.This activation is a consequence of a transient PH-TH dimerization induced by IP6, which promotes transphosphorylation of the kinase domains.Sequence comparisons with other Tec-family kinases suggest that activation by IP6 is unique to Btk.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular and Cell Biology, Howard Hughes Medical Institute, University of California, Berkeley, Berkeley, United States.

ABSTRACT
Bruton's tyrosine kinase (Btk), a Tec-family tyrosine kinase, is essential for B-cell function. We present crystallographic and biochemical analyses of Btk, which together reveal molecular details of its autoinhibition and activation. Autoinhibited Btk adopts a compact conformation like that of inactive c-Src and c-Abl. A lipid-binding PH-TH module, unique to Tec kinases, acts in conjunction with the SH2 and SH3 domains to stabilize the inactive conformation. In addition to the expected activation of Btk by membranes containing phosphatidylinositol triphosphate (PIP3), we found that inositol hexakisphosphate (IP6), a soluble signaling molecule found in both animal and plant cells, also activates Btk. This activation is a consequence of a transient PH-TH dimerization induced by IP6, which promotes transphosphorylation of the kinase domains. Sequence comparisons with other Tec-family kinases suggest that activation by IP6 is unique to Btk.

Show MeSH