Conformational Differences Among Solution Structures of the Type Iα, IIα and IIβ Protein Kinase A Regulatory Subunit Homodimers: Role of the Linker Regions

Vigil, Dominico; Blumenthal, Donald K.; Heller, William T.; Brown, Simon H. J.; Cánaves, Jaume M.; Taylor, Susan S.; Trewhella, Jill

doi:10.1016/j.jmb.2004.02.028

Cited by 58 publications

(75 citation statements)

References 55 publications

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“…Furthermore these three isoform holoenzyme structures (RIIb, RIb, and the RIa model) show distinct quaternary structures. This was suggested by early SAXS and SANS studies of the native holoenzymes in solution (115,116), but confirmed in the crystal structures. The holoenzymes are structurally distinct as well as functionally distinct (117).…”

Section: The Essential Elements Of the Hydrophobic Spine Architectusupporting

confidence: 59%

PKA and the Structural Kinome

Taylor

Kornev

2017

Period Biol

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Introduction. Although protein phosphorylation was discovered in the 1950's when casein was found to be a covalently modified phosphoprotein (1), it was not until the classic work of Krebs and Fischer with phosphorylase kinase (PhosK) that protein phosphorylation was discovered to be a regulatory mechanism (2). Over the ensuing decades we now appreciate that this is one of the major regulatory mechanisms in biology and that the eukaryotic protein kinases (EPKs) constitute one of the largest families encoded for by the human genome (3). Understanding the structure, function, and regulation of these proteins remains as one of the great challenges of the signaling community, and the importance of this superfamily is underscored by their therapeutic importance as drug targets (4, 5). As we think about the enormous complexity of the EPKs, which includes not only large membrane-spanning protein kinases such as the epidermal growth factor receptor (EGFR) (6) and the insulin receptor (InsR) (7, 8), as well as giant scaffold protein such as Titan (9), but also the multi-component signaling complexes such as mTOR (10, 11), it is important to recognize and appreciate the highly dynamic nature of the EPKs. They have evolved from the eukaryotic-like kinases (ELKs) (12, 13) to be molecular switches that are transiently and dynamically regulated. Their substrates are proteins, not small molecules, and unlike metabolic enzymes such as hexokinase and pyruvate kinase, they have not evolved to be efficient catalysts. In many cases, like MAP kinases (MAPKs), PKCs, and the non-receptor tyrosine kinases, dynamic translocation is a critical feature of their regulation while in other cases such as the EGFR the kinase remains localized to the plasma membrane but can be internalized as an endocytotic vesicle with its accessory machinery creating a transient signaling organelle (14). What is clear from all of these EPKs, however, is that they have not evolved to be efficient catalysts; they have evolved to be dynamic and highly regulated molecular switches. Kinome (1959Kinome ( -1979. Cyclic AMP-dependent protein kinase (PKA) was the second regulatory protein kinase to be discovered nearly a decade after PhosK (15). It was originally found as a contaminant of PhosK, and because phosphorylase kinase was its substrate it was initially called phosphorylase kinase kinase. The concept of kinase cascades was also thus embedded in those first two kinases where one kinase activated another. PhosK is a large multi-subunit kinase (a 4 b 4 g 4 d 4 ) that is dedicated exclusively to the phosphorylation of a single Ser near the Birth of the C-terminus of glycogen phosphorylase (16).Unlike PhosK, there are many other targets for PKA in the liver, but the fundamental concept of kinase cascades was revealed by these first two protein kinases. With the purification of the PKA catalytic (C) subunit (15) and the subsequent discovery of the PKA regulatory (R) subunits (17)(18)(19), it was quickly renamed cAMP-dependent protein kinase. Cyclic GMP-de...

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Section: The Essential Elements Of the Hydrophobic Spine Architectusupporting

confidence: 59%

PKA and the Structural Kinome

Taylor

Kornev

2017

Period Biol

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“…The difference in AKAP-binding specificity between RI and RII may be explained by the fact that the extreme N-terminus in the RI subunit is believed to be helical and that this additional helix folds back on to the four-helix bundle. Furthermore, the RIa homodimer is rather compact having a Y-like shape with a maximum diameter of 14 nm (Heller et al 2004), while the RIIa and RIIb dimers seem to be completely extended with a maximum diameter of nearly 20 nm (Vigil et al 2004). In addition, the RIa subunit undergoes a major conformational change when it associates with the catalytic subunit (Vigil et al 2005), while the RIIa subunits remain fully extended (Zhao et al 1998).…”

Section: A-kinase-anchoring Proteinsmentioning

confidence: 98%

“…Type I PKA is more sensitive to cAMP with an activation constant (K act ) of 50-100 nM of cAMP and was classically know to be mainly cytosolic; while about 75% of type II PKA is associated with organelles and specific cellular structures and it presents a K act of 200-400 nM of cAMP (Cadd et al 1990, Dostmann & Taylor 1991, Gamm et al 1996. Each R subunit of PKA contains an N-terminal docking and dimerization (D/D) domain, a PKA inhibitor site, and two tandem cAMP-binding domains (Heller et al 2004). The D/D domain is connected to cAMP-binding domain A by an extended, highly disordered linker that contains an autoinhibitory sequence and several putative phosphorylation sites.…”

Section: Camp-dependent Protein Kinasementioning

confidence: 99%

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Specificity and spatial dynamics of protein kinase A signaling organized by A-kinase-anchoring proteins

Pidoux

Taskén

2010

Journal of Molecular Endocrinology

157

144

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Protein phosphorylation is the most common post-translational modification observed in cell signaling and is controlled by the balance between protein kinase and phosphatase activities. The cAMP-protein kinase A (PKA) pathway is one of the most studied and well-known signal pathways. To maintain a high level of specificity, the cAMP-PKA pathway is tightly regulated in space and time. A-kinase-anchoring proteins (AKAPs) target PKA to specific substrates and distinct subcellular compartments providing spatial and temporal specificity in the mediation of biological effects controlled by the cAMP-PKA pathway. AKAPs also serve as scaffolding proteins that assemble PKA together with signal terminators such as phosphoprotein phosphatases and cAMP-specific phosphodiesterases as well as components of other signaling pathways into multiprotein-signaling complexes.

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“…Rapid data acquisition enables the experimenter to screen a large number of samples or conditions in a given slot of beam time (e.g. Vigil, Blumenthal, Brown et al, 2004;Vigil, Blumenthal, Heller et al, 2004;Mehboob et al, 2003;Telmer & Shilton, 2003) allowing more complex experiments to be contemplated than is usual at most existing facilities which are located on second-generation synchrotron sources. Furthermore, these rapid exposure times permit novel modes of data collection such as simultaneous liquid chromatography and SAXS measurements that may permit acquisition of interpretable data from unstable samples or multicomponent systems (Mathew et al, 2004).…”

Section: Performance For Saxsmentioning

confidence: 99%

The BioCAT undulator beamline 18ID: a facility for biological non-crystalline diffraction and X-ray absorption spectroscopy at the Advanced Photon Source

et al. 2004

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The 18ID undulator beamline of the Biophysics Collaborative Access Team at the Advanced Photon Source, Argonne, IL, USA, is a highperformance instrument designed for, and dedicated to, the study of partially ordered and disordered biological materials using the techniques of small-angle X-ray scattering, ®ber diffraction, and X-ray absorption spectroscopy. The beamline and associated instrumentation are described in detail and examples of the representative experimental results are presented.

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Conformational Differences Among Solution Structures of the Type Iα, IIα and IIβ Protein Kinase A Regulatory Subunit Homodimers: Role of the Linker Regions

Cited by 58 publications

References 55 publications

PKA and the Structural Kinome

PKA and the Structural Kinome

Specificity and spatial dynamics of protein kinase A signaling organized by A-kinase-anchoring proteins

The BioCAT undulator beamline 18ID: a facility for biological non-crystalline diffraction and X-ray absorption spectroscopy at the Advanced Photon Source

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