scholarly journals Multi-state recognition pathway of the intrinsically disordered protein kinase inhibitor by protein kinase A

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Cristina Olivieri ◽  
Yingjie Wang ◽  
Geoffrey C Li ◽  
Manu V S ◽  
Jonggul Kim ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Protein Kinase A ◽  
Nuclear Export ◽  
Kinase Inhibitor ◽  
Intrinsically Disordered Protein ◽  
Protein Kinase Inhibitor ◽  
State Recognition ◽  
Intrinsically Disordered ◽  
Disordered Protein ◽  
Kinase A

In the nucleus, the spatiotemporal regulation of the catalytic subunit of cAMP-dependent protein kinase A (PKA-C) is orchestrated by an intrinsically disordered protein kinase inhibitor, PKI, which recruits the CRM1/RanGTP nuclear exporting complex. How the PKA-C/PKI complex assembles and recognizes CRM1/RanGTP is not well understood. Using NMR, SAXS, fluorescence, metadynamics, and Markov model analysis, we determined the multi-state recognition pathway for PKI. After a fast binding step in which PKA-C selects PKI’s most competent conformations, PKI folds upon binding through a slow conformational rearrangement within the enzyme’s binding pocket. The high-affinity and pseudo-substrate regions of PKI become more structured and the transient interactions with the kinase augment the helical content of the nuclear export sequence, which is then poised to recruit the CRM1/RanGTP complex for nuclear translocation. The multistate binding mechanism featured by PKA-C/PKI complex represents a paradigm on how disordered, ancillary proteins (or protein domains) are able to operate multiple functions such as inhibiting the kinase while recruiting other regulatory proteins for nuclear export.

scholarly journals Protein Kinase Inhibitor Peptide as a Tool to Specifically Inhibit Protein Kinase A

2020 ◽  
Vol 11 ◽  
Author(s):  
Chong Liu ◽  
Ping Ke ◽  
Jingjing Zhang ◽  
Xiaoying Zhang ◽  
Xiongwen Chen
Keyword(s):  
Protein Kinase ◽  
Protein Kinase A ◽  
Kinase Inhibitor ◽  
Cyclic Adenosine Monophosphate ◽  
Adenosine Monophosphate ◽  
Protein Kinase Inhibitor ◽  
The Body ◽  
Specific Method ◽  
Inhibitor Peptide ◽  
Kinase A

The protein kinase enzyme family plays a pivotal role in almost every aspect of cellular function, including cellular metabolism, division, proliferation, transcription, movement, and survival. Protein kinase A (PKA), whose activation is triggered by cyclic adenosine monophosphate (cAMP), is widely distributed in various systems and tissues throughout the body and highly related to pathogenesis and progression of various kinds of diseases. The inhibition of PKA activation is essential for the study of PKA functions. Protein kinase inhibitor peptide (PKI) is a potent, heat-stable, and specific PKA inhibitor. It has been demonstrated that PKI can block PKA-mediated phosphorylase activation. Since then, researchers have a lot of knowledge about PKI. PKI is considered to be the most effective and specific method to inhibit PKA and is widely used in related research. In this review, we will first introduce the knowledge on the activation of PKA and mechanisms related on the inhibitory effects of PKI on PKA. Then, we will compare PKI-mediated PKA inhibition vs. several popular methods of PKA inhibition.

Protein kinase inhibitor β enhances the constitutive activity of G-protein-coupled zinc receptor GPR39

2014 ◽  
Vol 462 (1) ◽  
pp. 125-132 ◽  
Author(s):  
Zsuzsa Kovacs ◽  
Teresa Schacht ◽  
Ann-Kathrin Herrmann ◽  
Philipp Albrecht ◽  
Konstantinos Lefkimmiatis ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Protein Kinase A ◽  
G Protein ◽  
Inhibitory Activity ◽  
Kinase Inhibitor ◽  
Protein Kinase Inhibitor ◽  
Constitutive Activity ◽  
G Protein Coupled ◽  
Kinase A

Protein kinase A inhibitor β interacts with the G-protein-coupled zinc receptor GPR39 and increases its cytoprotective constitutive activity via Gα13, but has no effect on ligand-mediated activation of Gs and Gq regardless of its inhibitory activity on protein kinase A.

scholarly journals Regulation of NT-PGC-1α Subcellular Localization and Function by Protein Kinase A-dependent Modulation of Nuclear Export by CRM1

2010 ◽  
Vol 285 (23) ◽  
pp. 18039-18050 ◽  
Author(s):  
Ji Suk Chang ◽  
Peter Huypens ◽  
Yubin Zhang ◽  
Chelsea Black ◽  
Anastasia Kralli ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Subcellular Localization ◽  
Protein Kinase A ◽  
Nuclear Export ◽  
And Function ◽  
Kinase A

Cloning and mapping of human PKIB and PKIG, and comparison of tissue expression patterns of three members of the protein kinase inhibitor family, including PKIA

2000 ◽  
Vol 349 (2) ◽  
pp. 403-407 ◽  
Author(s):  
Lihua ZHENG ◽  
Long YU ◽  
Qiang TU ◽  
Min ZHANG ◽  
Hua HE ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Protein Kinase ◽  
Nuclear Export ◽  
Kinase Inhibitor ◽  
Expression Patterns ◽  
Nuclear Export Signal ◽  
Tissue Expression ◽  
Protein Kinase Inhibitor ◽  
The Other ◽  
Dependent Protein

Two novel members of the human cAMP-dependent protein kinase inhibitor (PKI) gene family, PKIB and PKIG, were cloned. The deduced proteins showed 70% and 90% identity with mouse PKIβ and PKIγ respectively. Both the already identified pseudosubstrate site and leucine-rich nuclear export signal motifs were defined from the 11 PKIs of different species. The PKIB and PKIG genes were mapped respectively to chromosome 6q21-22.1, using a radiation hybrid GB4 panel, and to chromosome 20q13.12-13.13, using a Stanford G3 panel. Northern-blot analysis of three PKI isoforms, including the PKIA identified previously, revealed significant differences in their expression patterns. PKIB had two transcripts of 1.9 kb and 1.4 kb. The former transcript was abundant in both placenta and brain and the latter was expressed most abundantly in placenta, highly in brain, heart, liver, pancreas, moderately in kidney, skeletal muscle and colon, and very little in the other eight tissues tested. PKIG was widely expressed as a 1.5-kb transcript with the highest level in heart, hardly detectable in thymus and peripheral blood leucocytes and was moderately expressed in the other tissues, with slightly different levels. However, PKIA was specifically expressed as two transcripts of 3.3 kb and 1.5 kb in heart and skeletal muscle. The distinct expression patterns of the three PKIs suggest that their roles in various tissues are probably different.

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