Low and Room Temperature X-ray Structures of Protein Kinase A Ternary Complexes Shed New Light on Its Activity

doi:https://doi.org/10.1107/S0907444912014886

Title: Low and Room Temperature X-ray Structures of Protein Kinase A Ternary Complexes Shed New Light on Its Activity

Abstract

Posttranslational protein phosphorylation by protein kinase A (PKA) is a ubiquitous signaling mechanism which regulates many cellular processes. A low temperature X-ray structure of the PKA catalytic subunit (PKAc) ternary complex with ATP and a 20-residue peptidic inhibitor (IP20) at the physiological Mg ²⁺ concentration of < 0.5mM revealed a single metal ion in the active site. The lack of a second metal in the low-temperature LT-PKAc-MgATP-IP20 renders the β- and γ- phosphoryl groups of ATP to be very flexibile, with high thermal B-factors. Thus, the second metal is crucial for tight positioning of the terminal phosphoryl for transfer to a substrate, as demonstrated by comparison of the former structure with LT-PKAc- Mg ₂ATP-IP20 complex. In addition to the kinase activity, PKAc is also able to slowly catalyze the hydrolysis of ATP using a water molecule as a substrate. We found that at room temperature under X-ray irradiation ATP can be readily and completely hydrolyzed into ATP and a free phosphate ion in the crystals of the ternary complex LT-PKAc- Mg ₂ATP-IP20. The cleavage of ATP may be aided by X-ray-born free hydroxyl radicals, a very reactive chemical species, that move quickly through the crystal at room temperature. The phosphatemore »« less

Authors:: Kovalevsky, Andrey Y.; Johnson, Hanna; Hanson, B. Leif; Waltman, Mary Jo; Fisher, S. Zoe; Taylor, Susan; Langan, Paul

Publication Date:: 2012-06-15

Research Org.:: Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States)

Sponsoring Org.:: USDOE

OSTI Identifier:: 1050341

DOE Contract Number:: AC05-00OR22725

Resource Type:: Journal Article

Journal Name:: Acta Crystallographica. Section D: Biological Crystallography

Additional Journal Information:: Journal Volume: 68; Journal Issue: 7; Journal ID: ISSN 0907-4449

Publisher:: International Union of Crystallography

Country of Publication:: United States

Language:: English

Subject:: 59 BASIC BIOLOGICAL SCIENCES; 60 APPLIED LIFE SCIENCES; ANIONS; CLEAVAGE; CONFORMATIONAL CHANGES; ELECTRON DENSITY; HYDROLYSIS; HYDROXYL RADICALS; IRRADIATION; PHOSPHATES; PHOSPHORYLATION; PHOSPHOTRANSFERASES; POSITIONING; PROTEINS; RESIDUES; TEMPERATURE DEPENDENCE; WATER

Citation Formats


                    Kovalevsky, Andrey Y., Johnson, Hanna, Hanson, B. Leif, Waltman, Mary Jo, Fisher, S. Zoe, Taylor, Susan, and Langan, Paul. Low and Room Temperature X-ray Structures of Protein Kinase A Ternary Complexes Shed New Light on Its Activity.  United States: N. p., 2012. 
        Web.  doi:10.1107/S0907444912014886.

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                    Kovalevsky, Andrey Y., Johnson, Hanna, Hanson, B. Leif, Waltman, Mary Jo, Fisher, S. Zoe, Taylor, Susan, & Langan, Paul. Low and Room Temperature X-ray Structures of Protein Kinase A Ternary Complexes Shed New Light on Its Activity.  United States.  https://doi.org/10.1107/S0907444912014886

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                    Kovalevsky, Andrey Y., Johnson, Hanna, Hanson, B. Leif, Waltman, Mary Jo, Fisher, S. Zoe, Taylor, Susan, and Langan, Paul. Fri .  
        "Low and Room Temperature X-ray Structures of Protein Kinase A Ternary Complexes Shed New Light on Its Activity".  United States.  https://doi.org/10.1107/S0907444912014886.

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@article{osti_1050341,

  title        = {Low and Room Temperature X-ray Structures of Protein Kinase A Ternary Complexes Shed New Light on Its Activity},

  author       = {Kovalevsky, Andrey Y. and Johnson, Hanna and Hanson, B. Leif and Waltman, Mary Jo and Fisher, S. Zoe and Taylor, Susan and Langan, Paul},

  abstractNote = {Posttranslational protein phosphorylation by protein kinase A (PKA) is a ubiquitous signaling mechanism which regulates many cellular processes. A low temperature X-ray structure of the PKA catalytic subunit (PKAc) ternary complex with ATP and a 20-residue peptidic inhibitor (IP20) at the physiological Mg2+ concentration of < 0.5mM revealed a single metal ion in the active site. The lack of a second metal in the low-temperature LT-PKAc-MgATP-IP20 renders the β- and γ- phosphoryl groups of ATP to be very flexibile, with high thermal B-factors. Thus, the second metal is crucial for tight positioning of the terminal phosphoryl for transfer to a substrate, as demonstrated by comparison of the former structure with LT-PKAc- Mg2ATP-IP20 complex. In addition to the kinase activity, PKAc is also able to slowly catalyze the hydrolysis of ATP using a water molecule as a substrate. We found that at room temperature under X-ray irradiation ATP can be readily and completely hydrolyzed into ATP and a free phosphate ion in the crystals of the ternary complex LT-PKAc- Mg2ATP-IP20. The cleavage of ATP may be aided by X-ray-born free hydroxyl radicals, a very reactive chemical species, that move quickly through the crystal at room temperature. The phosphate anion is clearly visible in the electron density maps; it remains in the active site, but slides about 2Å from its position in ATP toward Ala21 of IP20 that mimics the phosphorylation site. The phosphate, thus, pushes the peptidic inhibitor away from the product ADP, while resulting in dramatic conformational changes of IP20 terminal residues 24 and 25. X-ray structures of PKAc in complex with non-hydrolyzable ATP analog, AMPPNP, at both room and low temperatures demonstrated no temperature effects on the conformation and position of IP20.},

  doi          = {10.1107/S0907444912014886},

  url          = {https://www.osti.gov/biblio/1050341},
  journal      = {Acta Crystallographica. Section D: Biological Crystallography},

  issn         = {0907-4449},

  number       = 7,

  volume       = 68,

  place        = {United States},

  year         = {2012},

  month        = {6}

}

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Title: Low and Room Temperature X-ray Structures of Protein Kinase A Ternary Complexes Shed New Light on Its Activity

Abstract

Citation Formats

Influence of key residues on the reaction mechanism of the cAMP-dependent protein kinase journal, January 1999

Crystal structure of the catalytic subunit of cAMP-dependent protein kinase complexed with magnesium-ATP and peptide inhibitor journal, March 1993

Detection of Conformational Changes along the Kinetic Pathway of Protein Kinase A Using a Catalytic Trapping Technique † journal, September 1999

HKL -3000: the integration of data reduction and structure solution – from diffraction images to an initial model in minutes journal, July 2006

A QM/MM study of the phosphoryl transfer to the Kemptide substrate catalyzed by protein kinase A. The effect of the phosphorylation state of the protein on the mechanism journal, January 2011

The finer things in X-ray diffraction data collection journal, October 1999

cAMP-dependent protein kinase: Crystallographic insights into substrate recognition and phosphotransfer journal, February 1994

Features and development of Coot journal, March 2010

Crystallography & NMR System: A New Software Suite for Macromolecular Structure Determination journal, September 1998

Adenosine cyclic 3',5'-monophosphate dependent protein kinase: a new fluorescence displacement titration technique for characterizing the nucleotide binding site on the catalytic subunit journal, December 1983

Dynamics connect substrate recognition to catalysis in protein kinase A journal, October 2010

Dynamically committed, uncommitted, and quenched states encoded in protein kinase A revealed by NMR spectroscopy journal, April 2011

Version 1.2 of the Crystallography and NMR system journal, October 2007

Domain movements in protein kinases journal, January 1994

Structure of a peptide inhibitor bound to the catalytic subunit of cyclic adenosine monophosphate-dependent protein kinase journal, July 1991

2.2 Å refined crystal structure of the catalytic subunit of cAMP-dependent protein kinase complexed with MnATP and a peptide inhibitor journal, May 1993

How Does the cAMP-Dependent Protein Kinase Catalyze the Phosphorylation Reaction: An ab Initio QM/MM Study journal, February 2005

Insights into the Phosphoryl-Transfer Mechanism of cAMP-Dependent Protein Kinase from Quantum Chemical Calculations and Molecular Dynamics Simulations journal, January 2004

Poisson-Boltzmann model studies of molecular electrostatic properties of the cAMP-dependent protein kinase journal, August 1999

The Role of the Putative Catalytic Base in the Phosphoryl Transfer Reaction in a Protein Kinase: First-Principles Calculations journal, August 2003

Crystal Structure of a cAMP-dependent Protein Kinase Mutant at 1.26 Å: New Insights into the Catalytic Mechanism journal, February 2004

Interaction of Adenosine 5′-Triphosphate with Metal Ions X-ray Structure of Ternary Complexes Containing Mg(II), Ca(II), Mn(II), Co(II), ATP and 2,2′ -Dipyridylamine journal, December 1983

An ATP-Linked Structural Change in Protein Kinase A Precedes Phosphoryl Transfer under Physiological Magnesium Concentrations † journal, April 1999

Divalent metal ions influence catalysis and active-site accessibility in the camp-dependent protein kinase journal, December 1993

Magnetic resonance measurements of intersubstrate distances at the active site of protein kinase using substitution-inert cobalt(III) and chromium(III) complexes of adenosine 5'-(.beta.,.gamma.-methylenetriphosphate) journal, December 1980

Is There a Catalytic Base in the Active Site of cAMP-Dependent Protein Kinase? † journal, March 1997

Active and Inactive Protein Kinases: Structural Basis for Regulation journal, April 1996

Identification of a Partially Rate-Determining Step in the Catalytic Mechanism of cAMP-Dependent Protein Kinase: A Transient Kinetic Study Using Stopped-Flow Fluorescence Spectroscopy † journal, June 1997

PKA: a portrait of protein kinase dynamics journal, March 2004

ADP–Mg 2+ bound to the ATP-grasp domain of ATP-citrate lyase journal, September 2011

Influence of key residues on the reaction mechanism of the cAMP-dependent protein kinase
journal, January 1999

Crystal structure of the catalytic subunit of cAMP-dependent protein kinase complexed with magnesium-ATP and peptide inhibitor
journal, March 1993

Detection of Conformational Changes along the Kinetic Pathway of Protein Kinase A Using a Catalytic Trapping Technique ^†
journal, September 1999

HKL -3000: the integration of data reduction and structure solution – from diffraction images to an initial model in minutes
journal, July 2006

A QM/MM study of the phosphoryl transfer to the Kemptide substrate catalyzed by protein kinase A. The effect of the phosphorylation state of the protein on the mechanism
journal, January 2011

The finer things in X-ray diffraction data collection
journal, October 1999

cAMP-dependent protein kinase: Crystallographic insights into substrate recognition and phosphotransfer
journal, February 1994

Features and development of Coot
journal, March 2010

Crystallography & NMR System: A New Software Suite for Macromolecular Structure Determination
journal, September 1998

Adenosine cyclic 3',5'-monophosphate dependent protein kinase: a new fluorescence displacement titration technique for characterizing the nucleotide binding site on the catalytic subunit
journal, December 1983

Dynamics connect substrate recognition to catalysis in protein kinase A
journal, October 2010

Dynamically committed, uncommitted, and quenched states encoded in protein kinase A revealed by NMR spectroscopy
journal, April 2011

Version 1.2 of the Crystallography and NMR system
journal, October 2007

Domain movements in protein kinases
journal, January 1994

Structure of a peptide inhibitor bound to the catalytic subunit of cyclic adenosine monophosphate-dependent protein kinase
journal, July 1991

2.2 Å refined crystal structure of the catalytic subunit of cAMP-dependent protein kinase complexed with MnATP and a peptide inhibitor
journal, May 1993

How Does the cAMP-Dependent Protein Kinase Catalyze the Phosphorylation Reaction: An ab Initio QM/MM Study
journal, February 2005

Insights into the Phosphoryl-Transfer Mechanism of cAMP-Dependent Protein Kinase from Quantum Chemical Calculations and Molecular Dynamics Simulations
journal, January 2004

Poisson-Boltzmann model studies of molecular electrostatic properties of the cAMP-dependent protein kinase
journal, August 1999

The Role of the Putative Catalytic Base in the Phosphoryl Transfer Reaction in a Protein Kinase: First-Principles Calculations
journal, August 2003

Crystal Structure of a cAMP-dependent Protein Kinase Mutant at 1.26 Å: New Insights into the Catalytic Mechanism
journal, February 2004

Interaction of Adenosine 5′-Triphosphate with Metal Ions X-ray Structure of Ternary Complexes Containing Mg(II), Ca(II), Mn(II), Co(II), ATP and 2,2′ -Dipyridylamine
journal, December 1983

An ATP-Linked Structural Change in Protein Kinase A Precedes Phosphoryl Transfer under Physiological Magnesium Concentrations ^†
journal, April 1999

Divalent metal ions influence catalysis and active-site accessibility in the camp-dependent protein kinase
journal, December 1993

Magnetic resonance measurements of intersubstrate distances at the active site of protein kinase using substitution-inert cobalt(III) and chromium(III) complexes of adenosine 5'-(.beta.,.gamma.-methylenetriphosphate)
journal, December 1980

Is There a Catalytic Base in the Active Site of cAMP-Dependent Protein Kinase? ^†
journal, March 1997

Active and Inactive Protein Kinases: Structural Basis for Regulation
journal, April 1996

Identification of a Partially Rate-Determining Step in the Catalytic Mechanism of cAMP-Dependent Protein Kinase: A Transient Kinetic Study Using Stopped-Flow Fluorescence Spectroscopy ^†
journal, June 1997

PKA: a portrait of protein kinase dynamics
journal, March 2004

ADP–Mg ²⁺ bound to the ATP-grasp domain of ATP-citrate lyase
journal, September 2011