The coding sequence contains five regions showing a high degree of conservation in vertebrates, predominantly in exons 2, 5, 6, 7 and 8, but the sequences found in invertebrates show only distant resemblance to mammalian TP In humans, a common polymorphism involves the substitution of an arginine for a proline at codon position
The Guardian of the Genome p A Structural, Medical, and Pathological Enigma Our cells contain a number of proteins and pathways that define the cell function and fate. One specific protein, p53, has been shown to play a role in numerous cell processes.
This protein serves as a transcription factor whose responsibility is to inhibit the cell cycle by stopping cell growth and initiating apoptosis.
What could cause such a severe response as cell death? If p53 recognizes that there is an error, or a mutation, it will inhibit further damage to future cell line generations by triggering apoptosis, and effectively P53 guardian of genome the mutation from being passed on. Given the fact that p53 is vital for proper cell function, it is obvious to expect that when it does not have proper function, things can begin to go awry within an organism.
In cellular and molecular research, p53 is highlighted to be a specific point of focus. It is pertinent that researchers be able to describe the structure of p53, understand why some amino acid substitutions are more pathological than others, and map out the various cellular pathways in which the protein is involved; by gaining this knowledge, research could develop medical advancements that would give us the upper-hand into complex disorders, such as cancer.
When considering the unique structure of p53 we can see how its structure allows for specific DNA binding.
Residues 61 through 93 contain the PRR or proline-rich region.
The DNA-binding domain is on residues 94 throughand the other residues toward the end of the protein have an unknown structure. Regions through hold the tetramerization domains OD and these are connected to the CTD, or extreme carboxyl terminus 1.
These ligands are required for p53 to be able to sequence-specifically bind to DNA. Rainwater and colleagues tried replacing cysteine with serine. DNA binding does not occur with serine residues 2. There is most likely a correlation between the need for a better nucleophile and the ability to bind to the DNA.
Cysteine is more nucleophilic because of the large sulfur atom. Nucleophiles will readily attack causing the stabilization of the DNA binding site.
An adaptive evolutionary process has caused p53 to be intrinsically unstable; the protein will unfold at body temperature. This degradation might cause a folding and unfolding event, which could be linked to the amount of cancer mutations possible with this protein.
This thermodynamically unstable feature might also help with the binding to other proteins. The CTD or extreme carboxyl terminus is at the end region of the protein. This terminus is under the effects of intrinsic disorder meaning that the terminus is reactive and will lead to many different molecules binding to the site.
Due to this fact, the CTD will interact with many partner proteins. This relationship of binding causes the protein to go from disorder to order. The protein structure as a whole is very disordered and relies on other proteins for stability. P53 will bind to other proteins at the disordered amino-terminal transactivation domain.
Some binding takes place in the carboxyl terminus and a smaller amount occurs on the core domain. Understanding the binding of the protein will lead to understanding the whole structure of the protein.
Since the protein is still not fully understood, it is difficult to correctly design a structure for the protein. Some problems with the classification and structural identification of p53 is that the protein is either too flexible for crystallography, too big for NMR, but too small for cryo-electron microscopy.
By understanding the structure of the protein, new medicines can be designed to help with mutations and tumor suppression. Some of the current methods to correct p53 mutations include chemical reconstruction. Medicines are being designed that will help with tumor suppression by replacing the commonly mutated residues with ones that do not change characteristics of the protein.
Swapping a cysteine for a serine at sites other than DNA binding sites causes the protein to lack mutations. By utilizing medicine, the suppression system should function properly again. The majority of mutations that occur in p53 are based around the DNA binding region.Reviving the guardian of the genome: Small molecule activators of p Author links open overlay panel Daniel Nguyen Wenjuan Liao Shelya X.
Zeng Hua Lu. One such target and the focus of this review is the tumor suppressor p 2. p the guardian of the genome. The tumor suppressor p53 is the most recognized and researched protein in the. The TP53 gene provides instructions for making a protein called tumor protein p53 (or p53).
This protein acts as a tumor suppressor, which means that it regulates cell division by keeping cells from growing and dividing (proliferating) too fast or in an uncontrolled way. The p53 protein is located.
The Guardian Of The Genome The tumor protein p53 plays a pivotal role in the prevention of cancer formation. The human TP53 gene, which encodes this protein, is located on chromosome 17 (4). p 53 Kd (kilodalton) tumor suppressor protein known as TP53 coded by tumor suppresser gene pThe name p53 derived from its molecular size.
Why p53 is called p53 guardian of the genome? Also called as the “policeman of the oncogenes” referring to its role in conserving stability by preventing genome mutation. Called p53, the protein sounds the alarm to kill cells with DNA damage and prevent them from becoming cancerous—one reason why it has been called the “guardian of the genome.” But it is big and floppy, a molecular shapeshifter that is hard to follow with standard imaging tools.
In cases of DNA damage, there is triggering of expression of p53 gene whcich increases the production of p53 proteins.
These preoteins Prevent Cell from entering S phase of cell cycle and Allows time for the DNA repair to take .