PhysMath Central Blog
Eagle-eyed readers (or those with an RSS feed of latest articles) will have noticed that we have recently published a very interesting paper in PMC Biophysics by Tan and Luo. Handling editor Wei Yang explains below what makes this paper special.
Structural and functional implications of p53 missense cancer mutations
Yuhong Tan, Ray Luo
PMC Biophysics 2009, 2:5 (26 June 2009)
The transcription factor p53 is a central tumor suppressor protein that exerts its functions by relaying upstream stress signals, such as DNA damage, to downstream target genes that control DNA repair, cell cycle arrest, and apoptosis.
Close to 50% of all human cancers have p53 mutations, and 75% of those are missense mutations affecting the p53 DNA-binding core domain of approximately 200 amino acids.
These mutations inactivate the central p53 pathway leading to apoptosis, and allow cancerous cells to proliferate unchecked. Therefore, a long-held goal for anti-cancer therapy is to restore native function to p53 cancer mutants through pharmaceutical interventions, thereby activating apoptosis in cancerous cells and shrinking or killing the tumor.
However, without detailed analysis of the inactivation mechanisms in the cancer mutations, it is difficult to develop therapies targeting p53 cancer mutations.
Tan and Luo conducted a comprehensive computational analysis on all p53 core domain missense mutations to infer their likely inactivation mechanisms. They found that overall, 47.0% non-PRO/GLY mutants are stable and 36.3% mutants are unstable, 12.2% mutants are with 1.0kT < ΔΔG < 3.0kT. Only 4.5% mutants are with no conclusive predictions.
They correlated predicted stability with sequence, structure, and molecular contacts and found that the loss of protein-protein contacts may be an alternative cause for p53 inactivation, in addition to the loss of protein stability and loss of DNA contacts.
Nevertheless, their correlation analysis with clinical data shows that loss of stability and loss of DNA contacts are the two main inactivation mechanisms. Their correlation with functional data also shows that most mutations that retain functions are stable, and most mutations that gain functions are unstable, indicating destabilized and deformed p53 proteins are more likely to find new binding partners.
Posted by Chris Leonard at 14:36 Comments (0)
No charges for PMC Physics A through 2009
We are pleased to announce that PMC Physics A will not be levying any article processing charges for all articles accepted for publication between now and December 31st.
Please pass this news on to your colleagues as this is the perfect opportunity to have your worked published in a fully peer reviewed, open access journal at no cost to you.
View the editorial board here and submit your manuscript here.
Posted by Chris Leonard at 15:29 Comments (0)