Crystal Structures Reveal Hidden Domain Mechanics in Protein Kinase A (PKA)
Cyclic-AMP-dependent protein kinase A (PKA) is a critical enzyme involved in various signaling pathways that plays a crucial role in regulating cellular processes including metabolism, gene transcription, cell proliferation, and differentiation. In this study, the mechanisms of allostery in PKA were...
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| Format: | Article |
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MDPI AG
2023-10-01
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| Series: | Biology |
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| Online Access: | https://www.mdpi.com/2079-7737/12/11/1370 |
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| author | Colin L. Welsh Abigail E. Conklin Lalima K. Madan |
| author_facet | Colin L. Welsh Abigail E. Conklin Lalima K. Madan |
| author_sort | Colin L. Welsh |
| collection | DOAJ |
| description | Cyclic-AMP-dependent protein kinase A (PKA) is a critical enzyme involved in various signaling pathways that plays a crucial role in regulating cellular processes including metabolism, gene transcription, cell proliferation, and differentiation. In this study, the mechanisms of allostery in PKA were investigated by analyzing the vast repertoire of crystal structures available in the RCSB database. From existing structures of murine and human PKA, we elucidated the conformational ensembles and protein dynamics that are altered in a ligand-dependent manner. Distance metrics to analyze conformations of the G-loop were proposed to delineate different states of PKA and were compared to existing structural metrics. Furthermore, ligand-dependent flexibility was investigated through normalized B′-factors to better understand the inherent dynamics in PKA. The presented study provides a contemporary approach to traditional methods in engaging the use of crystal structures for understanding protein dynamics. Importantly, our studies provide a deeper understanding into the conformational ensemble of PKA as the enzyme progresses through its catalytic cycle. These studies provide insights into kinase regulation that can be applied to both PKA individually and protein kinases as a class. |
| first_indexed | 2024-03-09T17:00:35Z |
| format | Article |
| id | doaj.art-666ffd711c7a47e0aeb6f3e42654c08e |
| institution | Directory Open Access Journal |
| issn | 2079-7737 |
| language | English |
| last_indexed | 2024-03-09T17:00:35Z |
| publishDate | 2023-10-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Biology |
| spelling | doaj.art-666ffd711c7a47e0aeb6f3e42654c08e2023-11-24T14:30:05ZengMDPI AGBiology2079-77372023-10-011211137010.3390/biology12111370Crystal Structures Reveal Hidden Domain Mechanics in Protein Kinase A (PKA)Colin L. Welsh0Abigail E. Conklin1Lalima K. Madan2Department of Cellular and Molecular Pharmacology and Experimental Therapeutics, College of Medicine, Medical University of South Carolina, Charleston, SC 29425, USADepartment of Cellular and Molecular Pharmacology and Experimental Therapeutics, College of Medicine, Medical University of South Carolina, Charleston, SC 29425, USADepartment of Cellular and Molecular Pharmacology and Experimental Therapeutics, College of Medicine, Medical University of South Carolina, Charleston, SC 29425, USACyclic-AMP-dependent protein kinase A (PKA) is a critical enzyme involved in various signaling pathways that plays a crucial role in regulating cellular processes including metabolism, gene transcription, cell proliferation, and differentiation. In this study, the mechanisms of allostery in PKA were investigated by analyzing the vast repertoire of crystal structures available in the RCSB database. From existing structures of murine and human PKA, we elucidated the conformational ensembles and protein dynamics that are altered in a ligand-dependent manner. Distance metrics to analyze conformations of the G-loop were proposed to delineate different states of PKA and were compared to existing structural metrics. Furthermore, ligand-dependent flexibility was investigated through normalized B′-factors to better understand the inherent dynamics in PKA. The presented study provides a contemporary approach to traditional methods in engaging the use of crystal structures for understanding protein dynamics. Importantly, our studies provide a deeper understanding into the conformational ensemble of PKA as the enzyme progresses through its catalytic cycle. These studies provide insights into kinase regulation that can be applied to both PKA individually and protein kinases as a class.https://www.mdpi.com/2079-7737/12/11/1370protein kinasesprotein kinase (A)kinase structurecatalytic domainstructural dynamicscrystal B-factors |
| spellingShingle | Colin L. Welsh Abigail E. Conklin Lalima K. Madan Crystal Structures Reveal Hidden Domain Mechanics in Protein Kinase A (PKA) Biology protein kinases protein kinase (A) kinase structure catalytic domain structural dynamics crystal B-factors |
| title | Crystal Structures Reveal Hidden Domain Mechanics in Protein Kinase A (PKA) |
| title_full | Crystal Structures Reveal Hidden Domain Mechanics in Protein Kinase A (PKA) |
| title_fullStr | Crystal Structures Reveal Hidden Domain Mechanics in Protein Kinase A (PKA) |
| title_full_unstemmed | Crystal Structures Reveal Hidden Domain Mechanics in Protein Kinase A (PKA) |
| title_short | Crystal Structures Reveal Hidden Domain Mechanics in Protein Kinase A (PKA) |
| title_sort | crystal structures reveal hidden domain mechanics in protein kinase a pka |
| topic | protein kinases protein kinase (A) kinase structure catalytic domain structural dynamics crystal B-factors |
| url | https://www.mdpi.com/2079-7737/12/11/1370 |
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