title: Autoinhibition of Bruton's tyrosine kinase (Btk) and activation by soluble inositol hexakisphosphate.
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.
authors.affiliation: Department of Molecular and Cell Biology, Howard Hughes Medical Institute, University of California, Berkeley, Berkeley, United States.
authors.forename: Qi
authors.initials: Q
authors.lastname: Wang
authors.affiliation: Beryllium Inc, Boston, United States.
authors.forename: Erik M
authors.initials: EM
authors.lastname: Vogan
authors.affiliation: Department of Chemistry, University of California, Berkeley, Berkeley, United States.
authors.forename: Laura M
authors.initials: LM
authors.lastname: Nocka
authors.affiliation: Department of Molecular and Cell Biology, Howard Hughes Medical Institute, University of California, Berkeley, Berkeley, United States.
authors.forename: Connor E
authors.initials: CE
authors.lastname: Rosen
authors.affiliation: Department of Molecular and Cell Biology, Howard Hughes Medical Institute, University of California, Berkeley, Berkeley, United States.
authors.forename: Julie A
authors.initials: JA
authors.lastname: Zorn
authors.affiliation: Laboratory of Molecular Medicine, Harvard Medical School, Howard Hughes Medical Institute, Boston, United States.
authors.forename: Stephen C
authors.initials: SC
authors.lastname: Harrison
authors.affiliation: Department of Molecular and Cell Biology, Howard Hughes Medical Institute, University of California, Berkeley, Berkeley, United States.
authors.forename: John
authors.initials: J
authors.lastname: Kuriyan
mesh_terms: D000077329:Agammaglobulinaemia Tyrosine Kinase; D000494:Allosteric Regulation / Q000187:drug effects; D000818:Animals; D001665:Binding Sites; D055162:Biocatalysis / Q000187:drug effects; D002417:Cattle; D002462:Cell Membrane / Q000187:drug effects / Q000201:enzymology; D018360:Crystallography, X-Ray; D004789:Enzyme Activation / Q000187:drug effects; D050356:Lipid Metabolism / Q000187:drug effects; D051379:Mice; D008958:Models, Molecular; D010766:Phosphorylation / Q000187:drug effects; D010833:Phytic Acid / Q000494:pharmacology*; D055503:Protein Multimerization / Q000187:drug effects; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism*; D016315:Proto-Oncogene Proteins c-abl / Q000378:metabolism; D012995:Solubility; D012996:Solutions; D055672:Static Electricity; D013816:Thermodynamics; D018909:src Homology Domains
chemical_list: D012996:Solutions; D010833:Phytic Acid; D011505:Protein-Tyrosine Kinases; D000077329:Agammaglobulinaemia Tyrosine Kinase; C000625951:Btk protein, mouse; D016315:Proto-Oncogene Proteins c-abl
keywords: B-cell signalling; E. coli; biochemistry; biophysics; protein structure; structural biology; tyrosine kinase