Navigation Links
St. Jude study gives new insights into how cells accessorize their proteins
Date:9/18/2008

St. Jude Children's Research Hospital investigators have gained new insight into how the cell's vast array of proteins would instantly be reduced to a confusion of lethally malfunctioning molecules without a system for proteins to "accessorize" in order to regulate their function.

Just as eyeglasses improve vision, a coat provides warmth or an umbrella wards off rain, cells use a set of proteins called ubiquitin-like proteins (UBLs) as accessories that adapt their function as needed in the cell. Now St. Jude scientists have discovered how the function of a protein called cullin-RING changes when it wears the UBL accessory called NEDD8.

The researcher's findings, published in the Sept. 19, 2008, issue of the journal "Cell," reveal that NEDD8 changes the shape of cullin-RING to activate it to perform its function. The researchers found that when NEDD8 attaches, it transforms cullin-RING into a kind of molecular valet that can then attach a different accessory (ubiquitin) onto other proteins to foster the myriad of biochemical reactions that enable life.

"The ubiquitination machinery is critical for the cell's proteins to be able to function as necessary in a given environment. One of the major functions of ubiquitin is to mark a protein for disposal when its job is done," said Brenda Schulman, Ph.D., associate member in the St. Jude Structural Biology and Genetics and Tumor Cell Biology departments and Howard Hughes Medical Institute (HHMI) investigator. "Understanding ubiquitination can give us important knowledge about such biological processes as cell division, embryonic development and immune function." Schulman is the paper's senior author.

"Basic insights into ubiquitination could ultimately have clinical application, because defects in the machinery have been implicated in cancers, neurodegenerative disorders and some viral infections," said David Duda, Ph.D., the paper's co-first author and HHMI research specialist in Schulman's lab.

Schulman and her colleagues study the enzymatic machinery that manages the accessorizing process, whether the accessory is NEDD8 or ubiquitin. Both molecules depend on specialized cadres of enzymatic valets that attach them to their correct targets.

One question the researchers addressed about the NEDD8-attaching machinery was how NEDD8 can make a considerable molecular leap to cullin-RING from the previous enzyme in the cadre that manages the attachment process. Also, the researchers wanted to understand how, once NEDD8 attaches to cullin-RING, it activates the enzyme to attach ubiquitin to its target protein. In this activation process NEDD8 also somehow thwarts the action of another molecule called CAND1, which normally inhibits cullin-RING.

"It is important to solve these lingering mysteries to give greater insights into this critically important process in the cell," said Daniel Scott, Ph.D., the paper's co-first author and HHMI research specialist in Schulman's lab.

In their experiments, the researchers crystallized cullin-RING proteins both with and without modification by NEDD8 attachment. They then subjected the crystals to structural analysis using X-ray crystallography. In this widely used technique, X-rays are directed through the crystal of a protein to be analyzed and its structure deduced from the pattern of diffraction of the X-rays.

Comparison of the two structures revealed that, when NEDD8 attaches to cullin-RING, it dramatically modifies the conformation of the enzyme, causing it to blossom from a "closed" to an "open" state. This open state eliminates the binding site for the inhibitor CAND1, activating cullin-RING to then put ubiquitin onto a different target protein. The open state also frees a key component of the cullin-RING, called RING, making it flexible enough to function, helping cullin-RING transfer ubiquitin to its target protein.

Schulman said that their findings with NEDD8 and cullin-RING have broader significance for detailed understanding of the workings of the intricate ubiquitination machinery.

"The whole process of attaching ubiquitinor any of this family of UBLsto their targets involves moving a protein onto other proteins to regulate their activity," she said. "And in many cases, this process is probably regulated by just the kind of conformational change that our findings reveal. So, we believe that these findings offer overall insight into how conformational change can activate these kinds of ligases."


'/>"/>

Contact: Summer Freeman
summer.freeman@stjude.org
901-595-3061
St. Jude Children's Research Hospital
Source:Eurekalert

Related biology news :

1. Duke to lead new NSF, EPA center to study the environmental implications of nanotechnology
2. NSF funds multi-university center to study environmental implications of nanotechnology
3. Study finds ATV guidelines inadequate
4. Flatworm helps researchers study stem cells and cancer
5. Study reveals how viruses collectively decide the fate of a bacterial cell
6. UC Riverside botanist to study role of plants in southern Californias drought
7. Book breaks new ground in the study of economics and forest threats management
8. As Andean glacier retreats, tiny life forms swiftly move in, CU-Boulder study shows
9. Rhode Island Hospital study finds link between obesity, type 2 diabetes and neurodegeneration
10. What a sleep study can reveal about fibromyalgia
11. Biological invasions increasing due to freshwater impoundments, says CU-Boulder study
Post Your Comments:
*Name:
*Comment:
*Email:
(Date:3/15/2016)... , March 15, 2016 Yissum Research ... the technology-transfer company of the Hebrew University, announced today ... remote sensing technology of various human biological indicators. Neteera ... $2.0 million from private investors. ... on the detection of electromagnetic emissions from sweat ducts, ...
(Date:3/11/2016)... , March 11, 2016 ... new market research report "Image Recognition Market by Technology ... (Marketing and Advertising), by Deployment Type (On-Premises and Cloud), ... To 2022", published by MarketsandMarkets, the global market is ... to USD 29.98 Billion by 2020, at a CAGR ...
(Date:3/9/2016)... 9, 2016 Nigeria ... more than 23,000 public service employees either did not ... their salary unlawfully.    --> Nigeria ... that more than 23,000 public service employees either did ... receiving their salary unlawfully.    --> DERMALOG, ...
Breaking Biology News(10 mins):
(Date:4/29/2016)... , April 29, 2016 ... Transparency Market Research "Separation Systems for Commercial Biotechnology ... Trends, and Forecast 2015 - 2023", the separation ... US$ 10,665.5 Mn in 2014 and is projected ... 2015 to 2023 to reach US$ 19,227.8 Mn ...
(Date:4/28/2016)... April 28, 2016 The report ... Brayton Cryocoolers), Service (Technical Support, Product Repairs & Refurbishment, ... Global Forecast to 2022", published by MarketsandMarkets, the global ... by 2022, at a CAGR of 7.29% between 2016 ... Tables and 94 Figures spread through 159 Pages and ...
(Date:4/28/2016)... Connecticut (PRWEB) , ... April 28, 2016 , ... ... Group, Inc., will hold an open house for regional manufacturers at its Maple ... displays from Tsugami, Okuma, Hardinge Group, Chiron and Trumpf. Almost 20 leading ...
(Date:4/27/2016)... , April 27, 2016 ... (CSE: NSK) (OTCPink: NSKQB) ( Frankfurt ... an ihre Pressemitteilung vom 13. August 2015 die ... ihre Finanzen um zusätzliche 200.000.000 Einheiten auf 400.000.000 ... Dollar zu bringen. Davon wurden 157.900.000 Einheiten mit ...
Breaking Biology Technology: