The permanent interplay of protein production and degradation is a major driver of cellular metabolism. A key mechanism of this regulation is the labeling of proteins with ubiquitin, a small polypeptide that plays important roles in many pathways, but also acts as a signal for protein degradation.
Ubiquitination can be reversed by a group of enzymes, the so-called deubiquitinases, which are able to rescue the proteins. In cancer cells these opposing processes are assumed to be out of balance. Deubiquitinases have therefore emerged in recent years as promising drug targets for cancer therapy.
The study focused specifically on the deubiquitinases USP25 and USP28. Both enzymes are important for the progression of various types of tumors. The research provides important insights into the structure and function of the two deubiquitinases. Using X-ray crystallography, the group was able to solve the three-dimensional structure of the central catalytic domains of both evolutionarily closely related enzymes and they uncovered similarities as well as crucial differences.
"It was surprising to discover that USP25, despite its structural similarity to USP28, is inactive in the isolated form (in vitro) as well as in cells (in vivo), and that there is a correlation between the oligomeric state and its activity," says the author. The researchers' analysis showed that the inactive USP25 forms a tetramer, a molecular complex of four-subunits. In contrast, USP28 exists as a constitutively active dimer, a molecular complex of two identical subunits. "By inserting alterations, found in cancer cells, we were able to show that the USP25 tetramer dissociates into two USP28-like dimers, thereby abolishing the auto-inhibition of the enzyme," reports another author.
This knowledge provides the molecular basis for the development of new and highly specific anti-cancer drugs, with a low risk of side-effects. "On the one hand, new approaches have been identified that could, for example, be used to develop tailor-made drugs targeting specifically USP28, thereby preventing inhibition of USP25, which is important for the immune response," says the author. "On the other hand, specific targeting of the already per se inhibited USP25 seems feasible by preventing its activation," adds the other author.
https://www.uni-wuerzburg.de/en/rvz/rvz-news/single/news/substantial-differences-between-the-tumor-promoting-enzymes-usp25-and-usp28-identified/
https://www.sciencedirect.com/science/article/abs/pii/S1097276519301406?via%3Dihub
Regulating activities of tumor-promoting deubiquitinases
- 1,692 views
- Added
Edited
Latest News
Abusive drugs hijack natura…
By newseditor
Posted 23 Apr
Mechanism of action of the…
By newseditor
Posted 23 Apr
Role of fat in rare neurolo…
By newseditor
Posted 23 Apr
How protein synthesis in de…
By newseditor
Posted 22 Apr
Atlas of mRNA variants in d…
By newseditor
Posted 22 Apr
Other Top Stories
Spicy molecule inhibits growth of breast cancer cells
Read more
Tumor cells move differently than normal ones
Read more
Role of fat utilization (beta-oxidation) in cancer spread!
Cancer cells spread to other sites in the body through promoting the growth of new 'roads' to travel on. In a study to be published in the top scientific journal, Nature, an international and multidisciplinary team of researchers, discovered how a shift to increased fat utilization is required for the development and growth of these 'roads', termed lymphatic vessels - a special kind of blood vessels…
Read more
Personalizing cancer treatment- patients sensitive to new type of c…
Read more
Naturally occurring mechanism of cancer drug-resistance may itself…
Read more
Protocols
A programmable targeted pro…
By newseditor
Posted 23 Apr
MemPrep, a new technology f…
By newseditor
Posted 08 Apr
A tangible method to assess…
By newseditor
Posted 08 Apr
Stem cell-derived vessels-o…
By newseditor
Posted 06 Apr
Single-cell biclustering fo…
By newseditor
Posted 01 Apr
Publications
Exploiting pancreatic cance…
By newseditor
Posted 23 Apr
Structure of antiviral drug…
By newseditor
Posted 23 Apr
Type-I-interferon-responsiv…
By newseditor
Posted 23 Apr
Selenium, diabetes, and the…
By newseditor
Posted 23 Apr
Long-term neuropsychologica…
By newseditor
Posted 23 Apr
Presentations
Hydrogels in Drug Delivery
By newseditor
Posted 12 Apr
Lipids
By newseditor
Posted 31 Dec
Cell biology of carbohydrat…
By newseditor
Posted 29 Nov
RNA interference (RNAi)
By newseditor
Posted 23 Oct
RNA structure and functions
By newseditor
Posted 19 Oct
Posters
A chemical biology/modular…
By newseditor
Posted 22 Aug
Single-molecule covalent ma…
By newseditor
Posted 04 Jul
ASCO-2020-HEALTH SERVICES R…
By newseditor
Posted 23 Mar
ASCO-2020-HEAD AND NECK CANCER
By newseditor
Posted 23 Mar
ASCO-2020-GENITOURINARY CAN…
By newseditor
Posted 23 Mar