Autoinhibition of Bruton's tyrosine kinase (Btk) and activation by soluble inositol hexakisphosphate
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...
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| Format: | Article |
| Language: | English |
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eLife Sciences Publications Ltd
2015-02-01
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| Series: | eLife |
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| Online Access: | https://elifesciences.org/articles/06074 |
| _version_ | 1811201068502089728 |
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| author | Qi Wang Erik M Vogan Laura M Nocka Connor E Rosen Julie A Zorn Stephen C Harrison John Kuriyan |
| author_facet | Qi Wang Erik M Vogan Laura M Nocka Connor E Rosen Julie A Zorn Stephen C Harrison John Kuriyan |
| author_sort | Qi Wang |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-12T02:15:50Z |
| format | Article |
| id | doaj.art-8e8d6a00ebf74762849d3409c8279eda |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-12T02:15:50Z |
| publishDate | 2015-02-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-8e8d6a00ebf74762849d3409c8279eda2022-12-22T03:52:16ZengeLife Sciences Publications LtdeLife2050-084X2015-02-01410.7554/eLife.06074Autoinhibition of Bruton's tyrosine kinase (Btk) and activation by soluble inositol hexakisphosphateQi Wang0Erik M Vogan1Laura M Nocka2Connor E Rosen3Julie A Zorn4Stephen C Harrison5John Kuriyan6Department of Molecular and Cell Biology, Howard Hughes Medical Institute, University of California, Berkeley, Berkeley, United States; California Institute for Quantitative Biosciences, University of California, Berkeley, Berkeley, United StatesBeryllium Inc, Boston, United States; Laboratory of Molecular Medicine, Harvard Medical School, Howard Hughes Medical Institute, Boston, United StatesDepartment of Chemistry, University of California, Berkeley, Berkeley, United StatesDepartment of Molecular and Cell Biology, Howard Hughes Medical Institute, University of California, Berkeley, Berkeley, United States; California Institute for Quantitative Biosciences, University of California, Berkeley, Berkeley, United StatesDepartment of Molecular and Cell Biology, Howard Hughes Medical Institute, University of California, Berkeley, Berkeley, United States; California Institute for Quantitative Biosciences, University of California, Berkeley, Berkeley, United StatesLaboratory of Molecular Medicine, Harvard Medical School, Howard Hughes Medical Institute, Boston, United StatesDepartment of Molecular and Cell Biology, Howard Hughes Medical Institute, University of California, Berkeley, Berkeley, United States; California Institute for Quantitative Biosciences, University of California, Berkeley, Berkeley, United States; Department of Chemistry, University of California, Berkeley, Berkeley, United States; Physical Biosciences Division, Lawrence Berkeley National Laboratory, Berkeley, United StatesBruton'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.https://elifesciences.org/articles/06074B-cell signallingtyrosine kinaseprotein structure |
| spellingShingle | Qi Wang Erik M Vogan Laura M Nocka Connor E Rosen Julie A Zorn Stephen C Harrison John Kuriyan Autoinhibition of Bruton's tyrosine kinase (Btk) and activation by soluble inositol hexakisphosphate eLife B-cell signalling tyrosine kinase protein structure |
| title | Autoinhibition of Bruton's tyrosine kinase (Btk) and activation by soluble inositol hexakisphosphate |
| title_full | Autoinhibition of Bruton's tyrosine kinase (Btk) and activation by soluble inositol hexakisphosphate |
| title_fullStr | Autoinhibition of Bruton's tyrosine kinase (Btk) and activation by soluble inositol hexakisphosphate |
| title_full_unstemmed | Autoinhibition of Bruton's tyrosine kinase (Btk) and activation by soluble inositol hexakisphosphate |
| title_short | Autoinhibition of Bruton's tyrosine kinase (Btk) and activation by soluble inositol hexakisphosphate |
| title_sort | autoinhibition of bruton s tyrosine kinase btk and activation by soluble inositol hexakisphosphate |
| topic | B-cell signalling tyrosine kinase protein structure |
| url | https://elifesciences.org/articles/06074 |
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