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

Journal Article · · eLife
DOI:https://doi.org/10.7554/elife.06074· OSTI ID:1628833
 [1];  [2];  [3];  [4];  [4];  [5];  [6]
  1. Department 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; DOE/OSTI
  2. Beryllium Inc, Boston, United States; Laboratory of Molecular Medicine, Harvard Medical School, Howard Hughes Medical Institute, Boston, United States
  3. Department of Chemistry, University of California, Berkeley, Berkeley, United States
  4. Department 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
  5. Laboratory of Molecular Medicine, Harvard Medical School, Howard Hughes Medical Institute, Boston, United States
  6. Department 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 States

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 (IP666

Research Organization:
Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States)
Sponsoring Organization:
USDOE Office of Science (SC); National Institutes of Health (NIH); Cancer Research Institute-Irvington Institute Fellowship Program
Grant/Contract Number:
AC02-05CH11231
OSTI ID:
1628833
Journal Information:
eLife, Journal Name: eLife Vol. 4; ISSN 2050-084X
Publisher:
eLife Sciences Publications, Ltd.Copyright Statement
Country of Publication:
United States
Language:
English

References (79)

The SH3 domain of Bruton's tyrosine kinase displays altered ligand binding properties when auto-phosphorylatedin vitro journal July 1999
Comparative Protein Structure Modeling Using Modeller journal September 2006
Structure of the binding site for inositol phosphates in a PH domain. journal October 1995
Flexibility and charge asymmetry in the activation loop of Src tyrosine kinases journal February 2009
Improved side-chain torsion potentials for the Amber ff99SB protein force field journal January 2010
Observation of inositol pentakis- and hexakis-phosphates in mammalian tissues by 31P NMR journal December 1987
Structure et polymorphisme des lipides: Étude par diffraction des rayons X du système formé de lipides de mitochondries de coeur de boeuf et d'Eau journal July 1967
Deficient expression of a B cell cytoplasmic tyrosine kinase in human X-linked agammaglobulinemia journal January 1993
Signal transduction by lymphocyte antigen receptors journal January 1994
Structure of the high affinity complex of inositol trisphosphate with a phospholipase C pleckstrin homology domain journal December 1995
VMD: Visual molecular dynamics journal February 1996
[20] Processing of X-ray diffraction data collected in oscillation mode book January 1997
Structural Basis for the Autoinhibition of c-Abl Tyrosine Kinase journal March 2003
Assessing the omnipotence of inositol hexakisphosphate journal March 2001
Structure of the PH domain from Bruton's tyrosine kinase in complex with inositol 1,3,4,5-tetrakisphosphate journal April 1999
Regulation of Btk Function by a Major Autophosphorylation Site Within the SH3 Domain journal May 1996
Structural Coupling of SH2-Kinase Domains Links Fes and Abl Substrate Recognition and Kinase Activation journal September 2008
Inositol Pyrophosphates Inhibit Akt Signaling, Thereby Regulating Insulin Sensitivity and Weight Gain journal December 2010
Organization of the SH3-SH2 Unit in Active and Inactive Forms of the c-Abl Tyrosine Kinase journal March 2006
Class I HDACs Share a Common Mechanism of Regulation by Inositol Phosphates journal July 2013
B cell antigen receptor signaling 101 journal July 2004
Regulation of BCR signaling journal June 2011
Protein kinases: evolution of dynamic regulatory proteins journal February 2011
Characterization of pp60c-src Tyrosine Kinase Activities Using a Continuous Assay: Autoactivation of the Enzyme Is an Intermolecular Autophosphorylation Process journal November 1995
Dimer Formation through Domain Swapping in the Crystal Structure of the Grb2-SH2−Ac-pYVNV Complex journal November 2000
Solution Structure of the SH3 Domain from Bruton's Tyrosine Kinase , journal March 1998
Domain Interactions in Protein Tyrosine Kinase Csk journal July 1999
Solution structure of the human BTK SH3 domain complexed with a proline-rich peptide from p120cbl journal January 2000
Occurrence and extracellular actions of inositol pentakis- and hexakisphosphate in mammalian brain journal December 1987
Back in the water: the return of the inositol phosphates journal May 2001
Structural basis for activation of human lymphocyte kinase Lck upon tyrosine phosphorylation journal December 1996
Direct stimulation of Bruton's tyrosine kinase by Gq-protein α-subunit journal September 1997
Three-dimensional structure of the tyrosine kinase c-Src journal February 1997
Crystal structure of the Src family tyrosine kinase Hck journal February 1997
Activation of the Sire-family tyrosine kinase Hck by SH3 domain displacement journal February 1997
Mechanism of auxin perception by the TIR1 ubiquitin ligase journal April 2007
Structure of HDAC3 bound to co-repressor and inositol tetraphosphate journal January 2012
Specific Btk inhibition suppresses B cell– and myeloid cell–mediated arthritis journal November 2010
Version 1.2 of the Crystallography and NMR system journal October 2007
The SYK tyrosine kinase: a crucial player in diverse biological functions journal May 2010
Membrane recognition by phospholipid-binding domains journal February 2008
Structural and functional insights into the regulation mechanism of CK2 by IP6 and the intrinsically disordered protein Nopp140 journal November 2013
Binding of beta gamma subunits of heterotrimeric G proteins to the PH domain of Bruton tyrosine kinase. journal November 1994
c-Abl Has High Intrinsic Tyrosine Kinase Activity That Is Stimulated by Mutation of the Src Homology 3 Domain and by Autophosphorylation at Two Distinct Regulatory Tyrosines journal August 2000
Bruton's Tyrosine Kinase Is a Toll/Interleukin-1 Receptor Domain-binding Protein That Participates in Nuclear Factor κB Activation by Toll-like Receptor 4 journal April 2003
Clustal W and Clustal X version 2.0 journal September 2007
GROMACS 4.5: a high-throughput and highly parallel open source molecular simulation toolkit journal February 2013
Structure of the PH domain and Btk motif from Bruton's tyrosine kinase: molecular explanations for X-linked agammaglobulinaemia journal June 1997
Conformation of full-length Bruton tyrosine kinase (Btk) from synchrotron X-ray solution scattering journal September 2003
PDB2PQR: an automated pipeline for the setup of Poisson-Boltzmann electrostatics calculations journal July 2004
PDB2PQR: expanding and upgrading automated preparation of biomolecular structures for molecular simulations journal May 2007
Deciphering key features in protein structures with the new ENDscript server journal April 2014
ZAP-70: An Essential Kinase in T-cell Signaling journal May 2010
T-Cell Signaling Regulated by the Tec Family Kinase, Itk journal June 2010
Improved Fourier coefficients for maps using phases from partial structures with errors journal May 1986
Improved methods for building protein models in electron density maps and the location of errors in these models journal March 1991
PHENIX : building new software for automated crystallographic structure determination journal October 2002
Generation, representation and flow of phase information in structure determination: recent developments in and around SHARP 2.0 journal October 2003
Coot model-building tools for molecular graphics journal November 2004
Overview of the CCP 4 suite and current developments journal March 2011
Improvement of macromolecular electron-density maps by the simultaneous application of real and reciprocal space constraints journal January 1993
Crystallography & NMR System: A New Software Suite for Macromolecular Structure Determination journal September 1998
High yield bacterial expression of active c-Abl and c-Src tyrosine kinases journal December 2005
Src kinase activation: A switched electrostatic network journal May 2006
Competing modes of self-association in the regulatory domains of Bruton's tyrosine kinase: Intramolecular contact versus asymmetric homodimerization journal January 2002
Bruton's tyrosine kinase: cell biology, sequence conservation, mutation spectrum, siRNA modifications, and expression profiling journal February 2005
ABL1 fusion genes in hematological malignancies: a review: ABL1 fusion genes in leukemia journal March 2011
The B-Cell Antigen Receptor: Structure and Function of Primary, Secondary, Tertiary and Quaternary Components journal April 1993
The Syk family of protein tyrosine kinases in T-cell activation and development journal October 1998
Positive Regulation of Itk PH Domain Function by Soluble IP4 journal May 2007
Activation of BTK by a Phosphorylation Mechanism Initiated by SRC Family Kinases journal February 1996
A Phospholipase C-Dependent Inositol Polyphosphate Kinase Pathway Required for Efficient Messenger RNA Export journal July 1999
Crystal structure of the mammalian Grb2 adaptor journal April 1995
Monovalent and Multivalent Ligation of the B Cell Receptor Exhibit Differential Dependence upon Syk and Src Family Kinases journal January 2013
Activation Loop Dynamics Determine the Different Catalytic Efficiencies of B Cell- and T Cell-Specific Tec Kinases journal August 2013
Tyrosine phosphorylation and activation of Bruton tyrosine kinase upon Fc epsilon RI cross-linking. journal August 1994
Role of a Novel PH-Kinase Domain Interface in PKB/Akt Regulation: Structural Mechanism for Allosteric Inhibition journal January 2009
Crystal Structure of Human AKT1 with an Allosteric Inhibitor Reveals a New Mode of Kinase Inhibition journal September 2010
Function of Bruton’s Tyrosine Kinase during B Cell Development Is Partially Independent of Its Catalytic Activity journal November 2003

Cited By (15)

IP6 is an HIV pocket factor that prevents capsid collapse and promotes DNA synthesis journal May 2018
Atomic view of the energy landscape in the allosteric regulation of Abl kinase journal September 2017
Btk SH2-kinase interface is critical for allosteric kinase activation and its targeting inhibits B-cell neoplasms journal May 2020
Plasmodium pseudo-Tyrosine Kinase-like binds PP1 and SERA5 and is exported to host erythrocytes journal May 2019
Structural and Functional Analysis of DDX41: a bispecific immune receptor for DNA and cyclic dinucleotide journal October 2016
Dynamic regulatory features of the protein tyrosine kinases journal August 2019
Structural mechanism for Bruton’s tyrosine kinase activation at the cell membrane journal April 2019
Inositol polyphosphates promote T cell-independent humoral immunity via the regulation of Bruton’s tyrosine kinase journal June 2019
Allosteric modulation of the catalytic VYD loop in Slingshot by its N-terminal domain underlies both Slingshot auto-inhibition and activation journal August 2018
The Src module: an ancient scaffold in the evolution of cytoplasmic tyrosine kinases journal July 2018
Structural mechanism for Bruton’s tyrosine kinase activation at the cell membrane journal April 2018
Btk SH2-kinase interface is critical for allosteric kinase activation and its targeting inhibits B-cell neoplasms posted_content December 2019
Adipocyte-specific deletion of Ip6k1 reduces diet-induced obesity by enhancing AMPK-mediated thermogenesis journal October 2016
IP6 is an HIV pocket factor that prevents capsid collapse and promotes DNA synthesis. text January 2018
Btk SH2-kinase interface is critical for allosteric kinase activation and its targeting inhibits B-cell neoplasms text January 2020

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