14-3-3 proteins were first discovered in the middle of the 1960s. They were identified as part of the acidic brain proteins family. As a group, these protons are considered to be conserved regulatory molecules. They exist amongst all eukaryotic cells within the brain. 14-3-3 proteins express a variety of abilities that allows them to bind to a plethora of signaling proteins. This includes, but is not limited to, phosphatases and kinases receptors. As of right now, the total number of signaling proteins that are identified as 14-3-3 ligands is over 200.
In mammals, you will find seven different genes that encode 14-3-3 proteins. In terms of structure, this protein has 9 or 10 alpha-helices. On their amino-termini helices, these proteins form hetero-dimer or homo-dimer interactions. You will find a variety of different modification domains within the 14-3-3 proteins. Typically, this includes phosphorylation & acetylation regions, divalent cation interaction, and proteolytic cleavage. If you were to compare these proteins to anything, then they maintain a very similar structure to the TPR superfamily.
14-3-3 Mechanism & Interactions
14-3-3 proteins work by binding to peptides. All of the interactions with different peptides happens along the binding groove. This groove is sometimes referred to as a cleft, it depends on the specific protein in question. Regardless of the terminology, it’s important to note that this area if amphipathic. This terminology means that it is a chemical compound with both water-loving and fat-loving properties.
While 14-3-3 proteins can bind to numerous peptides, three main ones commonly interact with these proteins. Frequently, 14-3-3 proteins have been discovered with a phosphorylated serine residue. It’s also similarly common to find threonine residue on them as well. However, it’s also not unheard of for non-phosphorylated ligands to bind with 14-3-3 proteins as well.
Due to the structural makeup of these proteins, they’re found to have various functions. Primarily, they help the process of class switch recombination. This process involves changing a B cell’s production of immunoglobulin from one type to a different type. The role played by 14-3-3 proteins is believed to be isoform-specific. In essence, they interact with another protein - AICDA. This protein helps create mutations in the DNA, and it interacts with 14-3-3 proteins to bring about the class switch recombination process.
Furthermore, the 14-3-3 family of phosphoserine binding proteins is thought to help regulate Cdc25C. The two things bind together when the right binding sites are generated. To do this, Cdc25C undergoes phosphorylation by CDS1 and CHEK1. When the binding site is available, 14-3-3 and Cdc25C bind together. While these proteins don’t do anything to the actual functionality of Cdc25C, it does sequester it to the cytoplasm. In doing so, this prevents any additional interactions. 14-3-3 also functions as a critical role player in a plethora of important regulatory processes. This includes mitogenic signal transduction, cell cycle control, and apoptotic cell death. The functions of this protein have become a hot topic for research due to the way 14-3-3 binds with such a diverse variety of signaling proteins.