Protein kinase C alpha (PKCα) is an enzyme that in humans is encoded by the PRKCA gene.
Functions
PKC-α shows an important regulatory effect of phospholipase D. Phospholipase D is located on the plasma membrane and is responsible for the hydrolysis of phosphatidylcholine to phosphatidic acid and choline. Studies have shown that phospholipase D may play a role in tumorigenesis by altering cellular events such as invasion and migration. Point mutations of specific phenylalanine residues have been shown to inhibit the ability of PKC-α to activate phospholipase D. The inhibitory effect of PKC-α is currently being studied. Researchers hope to learn how to use PKC-α to reduce phospholipase D activity and use this function to make anticancer drugs.
Structure
PKCα is a single-chain polypeptide with a molecular weight of about 78 KD. It consists of a regulatory domain at the N-terminus and a catalytic domain at the C-terminus. The two are linked by a "hinge region" that can be hydrolyzed by a protease. PKCα is composed of 4 conservative regions C1 to C4 and 5 variable regions V1 to V5. Each conservation region is equivalent to a functional element, and some variable regions also have partial function regulation. The V3 region is a hinge region connecting the regulatory domain and the catalytic domain. Activation of PKC exposes the V3 region and is easily hydrolyzed by proteases to produce active enzymes. There is a pseudo substrate site in front of the C1 region. Since the alanine replaces the serine or threonine at the phosphorylation site, it is not phosphorylated, thereby blocking the active center of the enzyme. This self-inhibition of pseudo substrate sites is one of the self-regulatory mechanisms common to many protein kinases. The C1 conserved region of PKCα is composed of two cysteine-rich zinc finger-like random repeats, of which there are 8 conserved residues C6H2 (HX12CX2CX4CX2CX4HX2CX7C), which form two zinc finger-like structures with two Zn2+. Ester and phorbol ester binding site. The C2 conserved region of PKCα is only the Ca2+ binding site and is regulated by Ca2+, while other PKC activities are not related to Ca2+. C3 and C4 are conserved regions located in the catalytic domain. The C3 region contains ATP binding sites. C4 contains a substrate binding site and a catalytic core sequence DFG. When the self-inhibitory pseudo substrate sequence in front of the C1 domain is not activated, it binds to the C4 substrate binding region, thereby blocking the binding of the true substrate. Certain conserved residues in the catalytic domain constitute the activation loop of the PKC catalytic core, which is involved in all aspects of substrate recognition, binding, and phosphate group transfer reactions.
Regulations
The protein kinase family is regulated by allosteric regulation, which is the binding of regulatory molecules that affect enzyme conformational changes and thereby alter enzyme activity. However, the main mode of PKC-α regulation involves its interaction with cell membranes, rather than direct interactions with specific molecules. The composition of the cell membrane also affects the function of PKC-α. The presence of calcium ions, magnesium ions, and diacylglycerols (DAG) is most important because they affect the hydrophobic domain of the membrane. The different concentrations of these three components make up longer or shorter lengths of the hydrophobic domain. A membrane with a long hydrophobic domain results in reduced activity because PKC-α is difficult to insert into the membrane. At low concentrations, the hydrophobic domain is shorter, which makes PKC-α easier to insert into the membrane and its activity increases.
Distribution of PKCα in normal tissues
Distribution in normal tissues PKCα belongs to the classical PKC subgroup, which is extremely widespread. It is expressed in almost all tissues and is involved in the regulation of cell functions. PKCα exists in myocardial tissue, and is abundant in cardiomyocytes of adult rats and suckling rats. PKCα is only found in neurons in the rat brain and has not been found in glial cells. On the thirteenth day of embryonic period, the motor neurons in the spinal cord and cervical spinal cord of rats have PKCα distribution around the nucleus, dendrites and axons of motor neurons that have just differentiated from neuroepithelium, and PKC in the nucleus gradually decreases in the future.
Distribution of PKCα in tumor tissue
Distribution in tumor tissues Most studies suggest that PKCα is highly expressed in tumor tissues, which can promote tumor cell proliferation, inhibit apoptosis and differentiation of tumor cells. Studies have found that PKCα is closely related to human gliomas. Baltuch et al. Found that the overexpression of PKCα is related to the malignancy of glioma cells in C6 rats.
Conclusions
PKC has different biological and enzymatic properties. There are certain differences in protein structure, gene structure, tissue distribution, and activators, and their roles in cell signal transmission are significantly different. Each subtype of PKC has complex functions and regulatory mechanisms, which are involved in the regulation of various physiological and pathological processes in the body. In recent years, the exploration of the overall function of PKC has gradually shifted to the separate study of members of the PKC family. The relationship between PKCα subtypes and signal transduction pathways, as well as the mechanisms of cell proliferation, differentiation, and apoptosis, have been studied in recent years. Research hotspot, its specific inhibitors will provide broad application prospects for clinical tumor suppression.
References
