Navigation Links
CSHL researchers solve structure of human protein critical for silencing genes
Date:5/25/2012

Cold Spring Harbor, N.Y. In a study published in the journal Cell on May 24, Cold Spring Harbor Laboratory (CSHL) scientists describe the three-dimensional atomic structure of a human protein bound to a piece of RNA that "guides" the protein's ability to silence genes. The protein, Argonaute-2, is a key player in RNA interference (RNAi), a powerful cellular phenomenon that has important roles in diverse biological processes, including an organism's development.

"Detailed knowledge of the structure of human Argonaute-2 and the way it interacts with its RNA guides will greatly improve our understanding of its biological mechanism of action," says CSHL Professor and HHMI Investigator Leemor Joshua-Tor, Ph.D., the study's leader. "Such precise structural information of the human Argonaute bound to an important RNA guide could potentially aid both basic research to understand the function of genes and also advance the development of RNAi as a therapeutic strategy in clinical settings."

Upon the activation of a gene within a cell, the gene's DNA is copied into a messenger RNA (mRNA) "transcript." The instructions encoded within this transcript are then used as a blueprint by the cell's protein synthesis machinery to generate a working protein. The gene is "silenced" or prevented from giving rise to the protein, however, when an Argonaute-2 protein that is bound to a small piece of "guide" RNAeither a short-interfering RNA or a microRNAintercepts the mRNA molecule. The guide RNA, whose nucleotide sequence matches that of the target mRNA, acts as a homing device that helps the Argonaute-2 protein zero in on the mRNA target.

A few years ago, Joshua-Tor collaborated with CSHL Professor and HHMI Investigator Gregory Hannon, Ph.D., who is also a co-author in this study, to show that Argonaute proteins, which are made up of different domains or parts, act like a pair of molecular scissors that slice up target mRNAs, thus preventing proteins from being made and enforcing the silencing of their genes. The discovery of the Argonautes' "slicer" activity stemmed in part from solving the crystal structure of an Argonaute protein from Pyrococcus furiosus, an archebacterium that thrives in extremely high temperatures.

"But we still know nothing about the biological functions or mechanisms of action of archebacterial Argonautes," says Joshua-Tor. "We therefore next focused on solving the structures of Argonautes from higher organisms such as mammals, in which Argonaute functions and target recognition are well documented."

Joshua-Tor's team and other research groups subsequently determined the atomic structures of individual parts of Argonaute proteins from higher organisms. While these studies revealed several important detailsfor example, the interaction between two parts of the Argonaute protein, called the PAZ and Mid domains, with the two ends of guide RNAsJoshua-Tor's goal was to solve the structure of the entire human Argonaute protein in complex with a single human guide RNA.

Overcoming a complicated series of technical challenges, her team has achieved this goal by analyzing the structure of a full-length human Argonaute-2 protein bound to a small RNA called miR-20a, which is known to play a role in cancer development. Although Argonautes from higher organisms diverged from their archebacterial cousins more than three billion years ago, the team's analysis shows remarkable similarity between the two structures, especially in the regions that are important for target recognition and slicing activity.

"Our structure shows that the guide RNA, which is anchored at both ends by the PAZ and Mid domains, kinks and twists its way through the structure of the entire protein, making several points of contact within each domain and with the linker loops that join them," explains Joshua-Tor. "The guide RNA thus acts like a backbone that rigidly locks together the otherwise flexible Argonaute protein and gives it stability."

The researchers speculate that the path threaded through the Argonaute by the guide RNAs could have evolved to maximize mutual stability, in turn making the protein-RNA complexes long-lived. This long life is critical for many biological processes that are mediated by Argonautes. "This is also the kind of information that might help us to design better synthetic guide RNAs for therapeutic use," explains Joshua-Tor. "It will also be useful to researchers who are trying to find more precise ways of blocking Argonaute activity."


'/>"/>

Contact: Hema Bashyam
bashyam@cshl.edu
516-367-6822
Cold Spring Harbor Laboratory
Source:Eurekalert  

Related biology news :

1. Researchers identify genetic markers to predict male fertility
2. University of Hawaii Cancer Center researchers create new anti-cancer drug
3. UCLA researchers develop way to strengthen proteins with polymers
4. Tufts Medical Center researchers finds marker in premies saliva predicts readiness to feed by mouth
5. Researchers aim to assemble the tree of life for all 2 million named species
6. Dartmouth researchers are learning how exercise affects the brain
7. Nottingham researchers lead worlds largest study into pre-eclampsia
8. Begin early: Researchers say water with meals may encourage wiser choices
9. Researchers look to relatives for clues in quest to develop sources of bioenergy
10. WSU researchers say genes and vascular risk modify effects of aging on brain and cognition
11. KIT researchers succeed in realizing a new material class
Post Your Comments:
*Name:
*Comment:
*Email:
Related Image:
CSHL researchers solve structure of human protein critical for silencing genes
(Date:3/1/2017)...  Aware, Inc. (NASDAQ: AWRE), a leading supplier of ... Moberg has resigned, effective March 3, 2017, as ... and Treasurer of Aware citing a desire to retire.  ... of the Board of Directors of Aware. ... and co-President, General Counsel has been named Chief Executive ...
(Date:2/26/2017)... Feb. 25, 2017  Securus Technologies, a leading ... for public safety, investigation, corrections and monitoring, announces ... Reentry. "Too often, too many offenders ... county jails are trying to tackle this ongoing ... friends and family members. While significant steps are underway, ...
(Date:2/16/2017)... Feb. 16, 2017  Genos, a community for ... it has received Laboratory Accreditation from the College ... presented to laboratories that meet stringent requirements around ... rigorous processes. "Genos is committed to ... practices. We,re honored to be receiving CAP accreditation," ...
Breaking Biology News(10 mins):
(Date:3/23/2017)... New York , March 23, 2017 ... blood plasma products and derivatives market is fragmented due to the presence ... players, such as Proliant, Thermo Fisher , and Sigma-Aldrich, compete ... leader, these three companies, collectively, held more than 76% of this ... ...
(Date:3/22/2017)... ... March 22, 2017 , ... Researchers face a fundamental ... samples to full-size tissues, bones, even whole organs to implant in people to ... blood deep into the developing tissue. , Current bioengineering techniques, including 3-D ...
(Date:3/22/2017)... 2017   iSpecimen ®, the marketplace ... Pathology Service (DPS), a full-service anatomic pathology reference ... United States , has joined a program offered ... (DHIN) to make human biospecimens and associated data ... program, announced in 2015 as a collaboration between iSpecimen ...
(Date:3/22/2017)... 22, 2017   VWR (NASDAQ: ... product and service solutions to laboratory and ... acquired EPL Archives, Inc., an international biorepository ... entire regulated product research, development and commercialization ... and ancillary services. EPL Archives is widely ...
Breaking Biology Technology: