Protein kinase A

Protein kinase A (PKA), also known as cAMP-dependent protein kinase, is a family of enzymes whose activity is dependent on cellular levels of cyclic AMP (cAMP). PKA is involved in controlling many cellular processes including metabolism, transcription, cell cycle progression, and apoptosis. The enzyme is a tetramer consisting of two regulatory subunits and two catalytic subunits.

Structure

PKA is a holoenzyme composed of two types of subunits: regulatory (R) and catalytic (C). There are two main forms of the regulatory subunit, RI and RII, each of which can exist in two isoforms, α and β, thus giving rise to four possible R subunits. The catalytic subunit also exists in several isoforms (Cα, Cβ, and Cγ). The combination of these subunits forms the active PKA holoenzyme. The active site of the catalytic subunit is where ATP binds and is utilized to transfer the γ-phosphate group of ATP to specific serine or threonine residues on target proteins.

Mechanism of Action

The activity of PKA is regulated by the intracellular concentration of cAMP. cAMP is synthesized from ATP by an enzyme called adenylate cyclase, which is activated by various signaling molecules. When cAMP levels increase, it binds to the regulatory subunits of PKA causing a conformational change that releases the active catalytic subunits. These catalytic subunits then phosphorylate target proteins on serine or threonine residues, altering their activity.

Functions

PKA plays a crucial role in a wide range of cellular processes. It is involved in the regulation of glycogen, sugar, and lipid metabolism. In the heart, PKA regulates heart rate and cardiac contractility by phosphorylating key proteins in cardiomyocytes. PKA also plays a role in gene expression by phosphorylating transcription factors such as CREB (cAMP response element-binding protein). Additionally, PKA is involved in the regulation of cell cycle and is implicated in the control of cell proliferation and differentiation.

Clinical Significance

Alterations in PKA activity have been linked to several diseases. Overactivation of PKA is associated with certain types of cancer, as it can lead to uncontrolled cell proliferation. Mutations in the regulatory subunit of PKA can lead to Carney complex, a syndrome characterized by skin pigmentation abnormalities, myxomas, and endocrine overactivity. Furthermore, PKA is a target for therapeutic intervention in heart disease and certain types of cancer.

Research

Research on PKA has provided insights into the molecular basis of its action and its role in health and disease. Studies on the structure of PKA have revealed how cAMP activates the enzyme and how the catalytic subunit phosphorylates target proteins. Ongoing research aims to develop specific inhibitors of PKA for therapeutic use in diseases where PKA activity is dysregulated.

Protein kinase A

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  Protein kinase A structure

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  Protein kinase A regulatory subunit II

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  Cyclic AMP