New molecules doom proteins with kiss of death

Like mobsters following strict orders, newly engineered molecules called "ubiquibodies" can mark specific proteins inside a cell for destruction – a molecular kiss of death that is paving the way for new drug therapies and powerful research tools.

Led by professor Matthew DeLisa, chemical engineers at Cornell University have developed a new type of antibody, called a "ubiquibody," which is an they have inserted into the natural process known as the ubiquitin-proteasome pathway (UPP). Their work appears in the March 16 issue of the Journal of Biological Chemistry and is highlighted in an analysis piece in the publication SciBX.

The UPP is the natural cellular pathway, or process, by which a cell gets rid of proteins it doesn't want anymore. A doomed gets tagged with a chain of a protein called ubiquitin, which is like a molecular sign that reads, "destroy me." The ubiquitin-tagged protein gets sent to the cell's proteasome – the cell's trash compactor – which breaks the protein into component amino acids.

DeLisa and colleagues hypothesized that this common process could be harnessed as a simple, tunable way to eliminate certain target proteins in a cell without having to mess with the genome to delete the protein using standard genetic engineering tools.

They did it by taking advantage of the modular nature of the UPP, which involves three enzymes called E1, E2 and E3. They modified a particular E3 enzyme called CHIP, giving only that part of the pathway a makeover.

They removed CHIP's natural binding domain, replacing it with an engineered binding protein – in this case an antibody fragment – that was created in the lab. The idea was to empower CHIP to put ubiquitin chains on any target, guided by the homing capabilities of the antibody fragment to seek out and bind to its specific target. They named the entire re-engineered molecule with the modified CHIP enzyme a ubiquibody.

To prove their concept, the researchers modified CHIP with a binding protein that targets the enzyme beta-galactosidase. They introduced DNA that encoded for their beta-galactosidase target into a human cell line, along with DNA that encoded their ubiquibodies with a for the beta-galactosidase enzyme. Sure enough, beta-galactosidase levels went down in the presence of the corresponding ubiquibodies.

"Our ability to redirect whatever protein you want to the proteasome is now made possible simply by swapping out different binding proteins with specificity for targets of interest to the researcher," DeLisa said.

Ubiquibodies could provide a powerful way to not only completely delete a protein from a cell to study that protein's effects, but to discover what happens if, say, only 50 percent of that protein is deleted. Current gene knockout technologies are all or nothing, DeLisa said. Ubiquibodies could fine-tune research around protein deletion or reduction.

The technology could also prove useful for future . In a cancer cell in which a certain protein has been identified as contributing to the disease, the ubiquibody could reduce or eliminate the protein from within by targeting that specific protein only, DeLisa said.

The therapeutic potential for ubiquibodies is being explored further in DeLisa's lab, with experiments on known to be present in diseases including Alzheimer's, cancer and Parkinson's.

More information: Journal of Biological Chemistry, DOI: 10.1074/jbc.M113.544825

add to favorites email to friend print save as pdf

Related Stories

Protein improves efficacy of tumor-killing enzyme

Apr 30, 2013

Scientists have devised a method for delivering tumor cell-killing enzymes in a way that protects the enzyme until it can do its work inside the cell. In their study in mBio, the online open-access journal of the American Societ ...

Scientists gain new insights into protein disposal

May 28, 2013

Cells have a sophisticated system to control and dispose of defective, superfluous proteins and thus to prevent damage to the body. Dr. Katrin Bagola and Professor Thomas Sommer of the Max Delbrück Center for Molecular Medicine ...

Recommended for you

Gamers helping in Ebola research

14 hours ago

Months before the recent Ebola outbreak erupted in Western Africa, killing more than a thousand people, scientists at the University of Washington's Institute for Protein Design were looking for a way to stop the deadly virus.

Carcinogenic role of a protein in liver decoded

16 hours ago

The human protein EGFR controls cell growth. It has mutated in case of many cancer cells or exists in excessive numbers. For this reason it serves as a point of attack for target-oriented therapies. A study ...

A new way to diagnose malaria, using magnetic fields

Aug 31, 2014

Over the past several decades, malaria diagnosis has changed very little. After taking a blood sample from a patient, a technician smears the blood across a glass slide, stains it with a special dye, and ...

User comments