The p53 protein acts as a guardian within human cells, preventing uncontrolled growth. It functions as a tumor suppressor, protecting cells from becoming cancerous by maintaining genome stability. This protein responds to various cellular stresses, such as DNA damage, by initiating processes that halt cell division or eliminate compromised cells. Its proper structure and function are therefore central to preventing the development of many human cancers.
The Building Blocks of p53
Each individual p53 protein, known as a monomer, is composed of several distinct regions. Human p53 is a protein made up of 393 amino acids, and these amino acids are organized into several functional segments. The N-terminal Transactivation Domain, located at one end of the protein, acts as an “on switch” that activates the expression of other genes.
Following this, a Proline-Rich Domain contributes to the protein’s stability and helps it participate in various signaling pathways within the cell. The central DNA-Binding Domain, often referred to as the “hand” of p53, is the most significant part. This domain, spanning residues approximately 94 to 292, binds to specific DNA sequences in the cell’s genetic material. It contains zinc molecules and arginine amino acid residues that are involved in this DNA interaction.
Further along the protein chain is the Oligomerization Domain, a segment that allows individual p53 proteins to connect with one another. Finally, the C-terminal Domain regulates the overall activity of the p53 protein.
Assembling the Functional Unit
For p53 to perform its tumor-suppressing role effectively, four individual p53 proteins, or monomers, must come together to form a larger, four-part complex called a tetramer. This assembly is facilitated by the Oligomerization Domain of each monomer, bringing the four units into a stable arrangement.
The p53 protein is only fully functional in this tetrameric form, as this multi-unit structure allows for stable and effective binding to DNA. Each of the four p53 subunits in the tetramer binds to a specific segment, or “quarter-site,” of the target DNA sequence. This cooperative interaction between the assembled units enhances the protein’s ability to bind to DNA, increasing its affinity by at least 50-fold and potentially up to 1000-fold compared to a single monomer.
Structural Changes From Mutations
When the TP53 gene, which provides the instructions for making the p53 protein, undergoes a mutation, it can lead to an error in its genetic code. This error can lead to the placement of an incorrect amino acid within the p53 protein chain during its production. Such a change can alter the protein’s three-dimensional shape, causing it to misfold. The TP53 gene is the most frequently mutated gene in human cancers, with over half of all cancers showing alterations in this gene.
Most of these cancer-related mutations are “missense” mutations, meaning a single amino acid is swapped for another, and they occur predominantly within the DNA-Binding Domain of p53. A misshapen DNA-Binding Domain can no longer bind to its target DNA sequences. Specific locations within this domain are known as “hotspot” mutations because they are frequently altered in various cancers.
Examples of these hotspot residues include Arg175, Gly245, Arg248, Arg249, Arg273, and Arg282, which collectively account for approximately 30% of all p53 mutations in human cancers. Mutations at positions like Arg273 and Arg248 are common and can compromise the protein’s ability to bind DNA. These structural alterations directly undermine p53’s protective capabilities.
The Consequences of a Damaged Structure
A misfolded p53 protein, especially one with a damaged DNA-Binding Domain, can no longer bind effectively to its target DNA sequences within the cell’s genome. This loss of binding prevents p53 from activating the genes it regulates. Normally, p53 activates genes that cause cell cycle arrest, such as p21, which can halt cell division at checkpoints like the G1 phase.
The compromised p53 also fails to activate genes involved in DNA repair. Furthermore, it cannot trigger genes responsible for apoptosis, a process of programmed cell death that eliminates severely damaged or abnormal cells. Without a functional p53, cells with DNA damage or other abnormalities are allowed to bypass these protective checkpoints.
These damaged cells can then continue to divide uncontrollably, accumulating further mutations. This unchecked proliferation of compromised cells is a step in the development and progression of cancer. The failure of p53 to execute its functions due to structural damage thus removes a barrier against tumor formation, allowing abnormal cells to survive and multiply.