Protein-devouring enzyme complex uses two different mechanisms to determine which targets to destroy

April 28, 2011
Figure 1: For intracellular proteins (yellow) tagged with ubiquitin chains (green), the tag and initiator region (red) must be close together for the tagged protein to be broken down (left). When the separation between these elements (orange) is too great, degradation becomes highly inefficient (right). Credit: 2011 Tomonao Inobe

The proteasome is the garbage-disposal system of the cell, enzymatically clearing away unwanted proteins. Since this requires the recognition of individual targets within the crowded cellular environment, it is critically important that molecules ‘marked for death’ are appropriately flagged.

This signal, known as the degron, is composed of two components: an unstructured ‘initiation region’ within the target and a recognition tag. This tag typically consists of a chain of ubiquitin , but some proteins get steered to the proteasome with the help of ubiquitin-binding ‘adaptor’ proteins. “These two pathways work in parallel with and independently from each other, and converge at the initiation step,” explains Tomonao Inobe of the RIKEN Brain Science Institute in Wako, Japan.

By analyzing the efficiency with which different synthetic protein constructs get degraded by the proteasome, Inobe and colleagues in Andreas Matouschek’s laboratory at Northwestern University in Illinois, USA, have uncovered important structural details of the recognition mechanisms used by the proteasome to manage these distinct pathways. 

The team’s initial experiments showed that the minimum length for the initiation region is shorter in proteins tagged with ubiquitin alone (Ub4) than those tagged with an adaptor-derived ubiquitin-like (UbL) domain. Similarly, they found that Ub4–mediated degradation was most efficient when these sites were close together, and was impaired by the insertion of rigid ‘spacer’ protein segments between the two degron components. With UbL-tagged constructs, however, degradation was maximized when these components were moderately separated.

Based on their data, the researchers concluded that these physical constraints arise because Ub4- and UbL-tagged proteins bind to completely different sites on the proteasome; ubiquitin binds very near to the digestion machinery, requiring the initiation region to be close by (Fig. 1), while the UbL-binding site is considerably farther away, and thus accommodates greater separation. Inobe compares this to how an electrical plug must match its outlet. “The proteasome can recognize different plugs,” he says, “but each one has to have the correct specific arrangement of prongs.”

Inobe hopes to better characterize the functional role of this distance restriction in the future, but suggests that this mechanism may enable this protein complex to achieve both direct destruction of individual proteins and the targeted degradation of specific molecules nestled within larger complexes. “The spacing rules fit well with the way these tags are used physiologically and help explain how substrates are selected for degradation or manage to escape the process,” says Inobe.

Explore further: Team finds most complex protein knot ever seen

More information: Inobe, T., et al. Defining the geometry of the two-component proteasome degron. Nature Chemical Biology 7, 161–167 (2011).

Related Stories

Team finds most complex protein knot ever seen

September 20, 2006

An MIT team has discovered the most complicated knot ever seen in a protein, and they believe it may be linked to the protein's function as a rescue agent for proteins marked for destruction.

Targeting key proteins of carcinogenesis

June 22, 2007

Misfolded and disused proteins are eliminated by a cellular shredder called the proteasome. The cell labels the proteins it wants to dispose with Ubiquitin (Ub) in order to avoid the unwanted degradation of still needed proteins. ...

Self-digestion as a means of survival

February 27, 2009

In times of starvation, cells tighten their belts: they start to digest their own proteins and cellular organs. The process - known as autophagy - takes place in special organelles called autophagosomes. It is a strategy ...

Searching for purpose in proteins

October 29, 2010

As scientists continue to acquire immense amounts of genomic and biochemical data from various organisms, they routinely find themselves confronted by proteins of known structure but enigmatic function—and resolving ...

Recommended for you

Force triggers gene expression by stretching chromatin

August 26, 2016

How genes in our DNA are expressed into traits within a cell is a complicated mystery with many players, the main suspects being chemical. However, a new study by University of Illinois researchers and collaborators in China ...

New method developed for producing some metals

August 25, 2016

The MIT researchers were trying to develop a new battery, but it didn't work out that way. Instead, thanks to an unexpected finding in their lab tests, what they discovered was a whole new way of producing the metal antimony—and ...

New electrical energy storage material shows its power

August 24, 2016

A powerful new material developed by Northwestern University chemist William Dichtel and his research team could one day speed up the charging process of electric cars and help increase their driving range.


Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.