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Structure of human protein critical for silencing genes solved by efvf thbtn
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Structure of human protein critical for silencing genes solved by EFVF THBTN
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| Article Posted: 12/09/2012 |
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Structure of human protein critical for silencing genes solved |
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"Detailed knowledge of the structure of human Argonaute-2 andthe way it interacts with its RNA guides will greatly improve ourunderstanding of its biological mechanism of action," saysCSHL Professor and HHMI Investigator Leemor Joshua-Tor, Ph.D., thestudy's leader. "Such precise structural information of thehuman Argonaute bound to an important RNA guide could potentiallyaid both basic research to understand the function of genes andalso advance the development of RNAi as a therapeutic strategy inclinical settings." Upon the activation of a gene within a cell, the gene's DNA iscopied into a messenger RNA (mRNA) "transcript." Theinstructions encoded within this transcript are then used as ablueprint by the cell's protein synthesis machinery to generate aworking protein. The gene is "silenced" or prevented fromgiving rise to the protein, however, when an Argonaute-2 proteinthat is bound to a small piece of "guide" RNA -- either ashort-interfering RNA or a microRNA -- intercepts the mRNAmolecule. The guide RNA, whose nucleotide sequence matches that ofthe target mRNA, acts as a homing device that helps the Argonaute-2protein zero in on the mRNA target. A few years ago, Joshua-Tor collaborated with CSHL Professor andHHMI Investigator Gregory Hannon, Ph.D., who is also a co-author inthis study, to show that Argonaute proteins, which are made up ofdifferent domains or parts, act like a pair of molecular scissorsthat slice up target mRNAs, thus preventing proteins from beingmade and enforcing the silencing of their genes.
The discovery ofthe Argonautes' "slicer" activity stemmed in part fromsolving 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 ormechanisms of action of archebacterial Argonautes," saysJoshua-Tor. "We therefore next focused on solving thestructures of Argonautes from higher organisms such as mammals, inwhich Argonaute functions and target recognition are welldocumented." Joshua-Tor's team and other research groups subsequently determinedthe atomic structures of individual parts of Argonaute proteinsfrom higher organisms. While these studies revealed severalimportant details -- for example, the interaction between two partsof the Argonaute protein, called the PAZ and Mid domains, with thetwo ends of guide RNAs -- Joshua-Tor's goal was to solve thestructure of the entire human Argonaute protein in complex with asingle human guide RNA.
Overcoming a complicated series of technical challenges, her teamhas achieved this goal by analyzing the structure of a full-lengthhuman Argonaute-2 protein bound to a small RNA called miR-20a,which is known to play a role in cancer development. AlthoughArgonautes from higher organisms diverged from their archebacterialcousins more than three billion years ago, the team's analysisshows remarkable similarity between the two structures, especiallyin the regions that are important for target recognition andslicing activity. "Our structure shows that the guide RNA, which is anchored atboth ends by the PAZ and Mid domains, kinks and twists its waythrough the structure of the entire protein, making several pointsof contact within each domain and with the linker loops that jointhem," explains Joshua-Tor. "The guide RNA thus acts likea backbone that rigidly locks together the otherwise flexibleArgonaute protein and gives it stability." The researchers speculate that the path threaded through theArgonaute by the guide RNAs could have evolved to maximize mutualstability, in turn making the protein-RNA complexes long-lived.This long life is critical for many biological processes that aremediated by Argonautes. "This is also the kind of informationthat might help us to design better synthetic guide RNAs fortherapeutic use," explains Joshua-Tor.
"It will also beuseful to researchers who are trying to find more precise ways ofblocking Argonaute activity.". I am an expert from Flavour and Fragrance, usually analyzes all kind of industries situation, such as screen printing kit , wheeled school backpack.
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