Nav: Home

Computer simulation reveals p53 weak spots and opens new avenues against cancer

September 07, 2016

p53 has long been known to be a key protein associated with many cancers. Its main function is to suppress tumor formation in the body, and thus protect it from cancer development. However, p53 is considerably less stable compared to its two cousins, p63 and p73. Of the three proteins, p53 is the one that has deviated the most from its ancestral invertebrate version. All three proteins have a region in their sequences that is responsible for recognizing and binding to target gene sequences, called a DNA binding domain (DBD).

Loss of p53 function, which in most cases is caused by destabilizing DBD mutations, is prone to aggregation and formation of amyloid fibrils, an outcome that may be explained by its high instability. Additionally, p53 aggregates have a prion-like behavior, in which p53 mutants highjack normal p53 molecules and convert them into the inactive amyloid form.

Over 90% of p53 mutations leading to cancer development are in the DBD, making it an important target for new cancer therapies. However, the tendency of p53 to aggregate and form amyloids is an obstacle for developing new strategies.

To gain a deeper understanding of the molecular features underlying p53 DBD stability, amyloid formation, and aggregation, a research group led by Jerson Lima Silva at the Federal University of Rio de Janeiro, Brazil, used microsecond timescale molecular dynamics (MD) simulations, a computational method used for studying the precise movements of atoms over time. MD allows researchers to study biological processes at a level of detail that is difficult to obtain by conventional experiments, providing new insights into how proteins work and predicting the origins of malfunction.

In a study entitled "Aggregation tendencies in the p53 family are modulated by backbone hydrogen bonds," published in the journal Scientific Reports, the group investigates the DBD sequence and structure of the three proteins (p53, p63, and p73) and shows that although they have similar sequences and structures in their respective DBDs, p53 is more prone to aggregation than the other two. The study shows that the innate structural weakness of p53 is explained by a high incidence of exposed backbone hydrogen bonds that are vulnerable to water attack. In contrast, p63 and p73 have better protected hydrogen bonds, and can resist water invasion and subsequent aggregation. "Our work sheds light on the molecular features underlying p53 DBD stability. The new knowledge can be used to develop strategies for stabilizing p53 and diminishing its tendency to form amyloids," says Elio A. Cino, first author of the study.

The group is now performing studies to investigate how amyloid formation induced by common p53 mutations is associated with breast cancer, glioblastomas, and other malignant tumors, and is testing specific small molecules and peptides as a way to diminish p53 aggregation and formation of amyloid fibrils.
-end-


Publicase Comunicação Científica

Related Proteins Articles:

Discovering, counting, cataloguing proteins
Scientists describe a well-defined mitochondrial proteome in baker's yeast.
Interrogating proteins
Scientists from the University of Bristol have designed a new protein structure, and are using it to understand how protein structures are stabilized.
Ancient proteins studied in detail
How did protein interactions arise and how have they developed?
What can we learn from dinosaur proteins?
Researchers recently confirmed it is possible to extract proteins from 80-million-year-old dinosaur bones.
Relocation of proteins with a new nanobody tool
Researchers at the Biozentrum of the University of Basel have developed a new method by which proteins can be transported to a new location in a cell.
Proteins that can take the heat
Ancient proteins may offer clues on how to engineer proteins that can withstand the high temperatures required in industrial applications, according to new research published in the Proceedings of the National Academy of Sciences.
Designer proteins fold DNA
Florian Praetorius and Professor Hendrik Dietz of the Technical University of Munich have developed a new method that can be used to construct custom hybrid structures using DNA and proteins.
The proteins that domesticated our genomes
EPFL scientists have carried out a genomic and evolutionary study of a large and enigmatic family of human proteins, to demonstrate that it is responsible for harnessing the millions of transposable elements in the human genome.
Rare proteins collapse earlier
Some organisms are able to survive in hot springs, while others can only live at mild temperatures because their proteins aren't able to withstand such extreme heat.
How proteins reshape cell membranes
Small 'bubbles' frequently form on membranes of cells and are taken up into their interior.

Related Proteins Reading:

Best Science Podcasts 2019

We have hand picked the best science podcasts for 2019. Sit back and enjoy new science podcasts updated daily from your favorite science news services and scientists.
Now Playing: TED Radio Hour

Anthropomorphic
Do animals grieve? Do they have language or consciousness? For a long time, scientists resisted the urge to look for human qualities in animals. This hour, TED speakers explore how that is changing. Guests include biological anthropologist Barbara King, dolphin researcher Denise Herzing, primatologist Frans de Waal, and ecologist Carl Safina.
Now Playing: Science for the People

#SB2 2019 Science Birthday Minisode: Mary Golda Ross
Our second annual Science Birthday is here, and this year we celebrate the wonderful Mary Golda Ross, born 9 August 1908. She died in 2008 at age 99, but left a lasting mark on the science of rocketry and space exploration as an early woman in engineering, and one of the first Native Americans in engineering. Join Rachelle and Bethany for this very special birthday minisode celebrating Mary and her achievements. Thanks to our Patreons who make this show possible! Read more about Mary G. Ross: Interview with Mary Ross on Lash Publications International, by Laurel Sheppard Meet Mary Golda...