Crystal structure of COP9 signalosome elucidated

August 13, 2014
Crystal structure of COP9 signalosome elucidated

Nicolas Thomä and his group at the Friedrich Miescher Institute for Biomedical Research have elucidated the crystal structure of the human COP9 signalosome, an important regulator of protein degradation. The crystal structure, published in today's issue of Nature, provides detailed insights into the molecular architecture of the eight-subunit complex and explains how specificity is achieved.

The COP9 signalosome (CSN) is a heavyweight in the disposal activities of a cell. Not only does it control about a fifth of all processes, it is also – quite literally – a large-sized complex composed of eight distinct proteins, all of which are required for its function.

Scientists led by Nicolas Thomä at the Friedrich Miescher Institute for Biomedical Research have now elucidated the of the entire human COP9 signalosome. This crystal structure provides detailed insights into the of the complex and makes it possible to draw conclusions about how it works.

CSN exerts its control through the regulation of numerous ligase enzymes known as Cullin RING E3 ubiquitin ligases (CRLs). This family of ubiquitin ligases, with approximately 200 members, adds small regulatory proteins (ubiquitins) to other proteins, thus targeting them for degradation. CSN inactivates CRLs by removing an activating protein, NEDD8, from their backbone.

With the aid of several complementary crystal structures, Thomä and his collaborators have now shown that six of the eight CSN proteins form a horseshoe-shaped ring. Within this ring, bundled together, lie CSN5 and CSN6. CSN5 is particularly important because it is the protein that removes NEDD8 once the ubiquitin ligase is bound. The scientists showed that still-inactive CSN5 is only guided to its appropriate place within the complex once the proteins forming the ring are assembled. Finally, the protein complex becomes functional when neddylated CRL is bound. This presence is sensed by CSN4, which communicates this state via CSN6 to CSN5, which in turn changes conformation to become enzymatically active.

"This induced fit mechanism ensures that CSN acts exclusively on neddylated CRLs, avoiding uncontrolled deneddylase activity," says Thomä. "Because CSN is also implicated in several cancers, the crystal structure gives us a better understanding of how specificity is generated, and how to interfere with CSN function. Last but not least, we are fairly proud to have been able to crystallize this heavyweight – obtaining the crystal structure of such a large nowadays still needs a lot of expertise, skill and maybe a little bit of luck."

Explore further: Mechanism of action of thalidomide elucidated

More information: Lingaraju GM, Bunker RD, Cavadini S, Hess D, Hassiepen U, Renatus M, Fischer ES, Thomä NH. Crystal structure of the human COP9 signalosome. Nature. 2014 July 16, online.

Related Stories

Mechanism of action of thalidomide elucidated

July 17, 2014

(Medical Xpress)—Scientists led by Nicolas Thomä at the Friedrich Miescher Institute for Biomedical Research have clarified the workings of thalidomide at the molecular level. Their analysis of various structures, published ...

When proteins change partners

September 11, 2009

Dieter Wolf, M.D., and colleagues at Burnham Institute for Medical Research (Burnham) have illuminated how competition between proteins enhances combinatorial diversity during ubiquitination (the process that marks proteins ...

Untying DNA knots

February 21, 2014

Structural biologists at the Friedrich Miescher Institute for Biomedical Research have resolved the 3D structure of a protein machine that plays an important part in the maintenance of genomic stability. They have revealed ...

Key worker in protein synthesis factory revealed

August 8, 2014

In all living cells, DNA makes RNA and RNA makes proteins. The molecular factory that translates the information from RNA to proteins is called the "ribosome" (shown in the accompanying movie). It is a large and sophisticated ...

Recommended for you

Stressed-out meerkats less likely to help group

September 22, 2017

Dominant female meerkats use aggression to keep subordinates from breeding, but a new study finds this negative behavior also can result in the latter becoming less willing to help within the group.

Why poison frogs don't poison themselves

September 21, 2017

Don't let their appearance fool you: Thimble-sized, dappled in cheerful colors and squishy, poison frogs in fact harbor some of the most potent neurotoxins we know. With a new paper published in the journal Science, scientists ...


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.