Small RNA molecules play role in regulation of genes
A team of Hopkins and Howard Hughes Medical Institute researchers, including Sergej Djuranovic and Rachel Green of the Department of Molecular Biology and Genetics, have discovered how microRNAs work to halt the production of certain proteins.
Although most cells in the human body contain the entire human genome, not every gene needs to, or should, be expressed at all times or in all cells. The regulation of gene expression is an important part of properly functioning cell life.
The team found that certain proteins in the Argonaute (AGO) family bind both messenger RNA (mRNA) and micro RNA (miRNA) or small interfering RNA (siRNA). This dual binding allows the Argonaute proteins to bind to a specific regions of mRNA (specifically the 5' cap, found at the beginning of the mRNA chain). When the protein complex binds to the mRNA, it can then prevent the mRNA from being translated into a protein.
Although it was known before that Argonaute proteins worked together with miRNA to halt protein translation, the Hopkins team is the first to propose a mechanism for this process.
After the miRNA (or siRNA) has been transcribed from the DNA code, the tiny RNA fragments are then loaded onto RISC complexes (RNA-induced silencing complexes). The combination of these two components, the small RNA and an AGO protein, gives the siRISCs and miRISCs their specificity, a specificity which will allow the complexes to target specific mRNAs for silencing.
Certain regions of the AGO proteins are especially important in this particular process. The proteins contain an N-terminal domain, a PAZ domain, which binds to the tail end of the siRNA or miRNA, a MID domain, which binds to the head of the siRNA or miRNA, and a PIWI domain for cutting up the mRNA strand.
Green and Djuranovic are especially interested in the MID domain, as it appears that in some AGO proteins this domain controls the binding of the AGOs themselves to specific mi- or si-RNA; the specific mi- or si-RNA binding then confers upon the AGO-small RNA complex a certain "choosiness" as to which mRNA will be cut by the AGO protein's catalytic PIWI domain. Green and colleagues have established that the MID domain, interacts with the small RNA's 5' head, causing an allosteric change in the AGO protein that then allows it to better interact with mRNA caps. This interaction will eventually lead to "interference," or the prevention of mRNA translation into protein in the ribosome. This would make sense as far as the AGOs structures would predict, as the AGO family contains a conserved feature called a Rossman-like fold. This is a common feature in other proteins that bind two targets allosterically.
Furthermore, differences in these MID domains might also be predictive of overall functional differences between various AGO proteins. Though related, not all AGOs behave in exactly the same way. Most, in fact, seem to group themselves according to specific activities and functions.
Most likely, allosteric control and functional diversity based upon MID domains work together in vivo to help cells monitor and regulate the levels of expression of various genes, allowing the cells to function properly.
Understanding these complex processes could in the future even have therapeutic or pharmacological potential. By understanding the mechanisms of translational regulation, scientists and doctors can potentially manipulate these processes in malfunctioning cells, such as cancerous cells, in vivo, allowing for the correction of derailed cellular mechanisms.
Although most cells in the human body contain the entire human genome, not every gene needs to, or should, be expressed at all times or in all cells. The regulation of gene expression is an important part of properly functioning cell life.
The team found that certain proteins in the Argonaute (AGO) family bind both messenger RNA (mRNA) and micro RNA (miRNA) or small interfering RNA (siRNA). This dual binding allows the Argonaute proteins to bind to a specific regions of mRNA (specifically the 5' cap, found at the beginning of the mRNA chain). When the protein complex binds to the mRNA, it can then prevent the mRNA from being translated into a protein.
Although it was known before that Argonaute proteins worked together with miRNA to halt protein translation, the Hopkins team is the first to propose a mechanism for this process.
After the miRNA (or siRNA) has been transcribed from the DNA code, the tiny RNA fragments are then loaded onto RISC complexes (RNA-induced silencing complexes). The combination of these two components, the small RNA and an AGO protein, gives the siRISCs and miRISCs their specificity, a specificity which will allow the complexes to target specific mRNAs for silencing.
Certain regions of the AGO proteins are especially important in this particular process. The proteins contain an N-terminal domain, a PAZ domain, which binds to the tail end of the siRNA or miRNA, a MID domain, which binds to the head of the siRNA or miRNA, and a PIWI domain for cutting up the mRNA strand.
Green and Djuranovic are especially interested in the MID domain, as it appears that in some AGO proteins this domain controls the binding of the AGOs themselves to specific mi- or si-RNA; the specific mi- or si-RNA binding then confers upon the AGO-small RNA complex a certain "choosiness" as to which mRNA will be cut by the AGO protein's catalytic PIWI domain. Green and colleagues have established that the MID domain, interacts with the small RNA's 5' head, causing an allosteric change in the AGO protein that then allows it to better interact with mRNA caps. This interaction will eventually lead to "interference," or the prevention of mRNA translation into protein in the ribosome. This would make sense as far as the AGOs structures would predict, as the AGO family contains a conserved feature called a Rossman-like fold. This is a common feature in other proteins that bind two targets allosterically.
Furthermore, differences in these MID domains might also be predictive of overall functional differences between various AGO proteins. Though related, not all AGOs behave in exactly the same way. Most, in fact, seem to group themselves according to specific activities and functions.
Most likely, allosteric control and functional diversity based upon MID domains work together in vivo to help cells monitor and regulate the levels of expression of various genes, allowing the cells to function properly.
Understanding these complex processes could in the future even have therapeutic or pharmacological potential. By understanding the mechanisms of translational regulation, scientists and doctors can potentially manipulate these processes in malfunctioning cells, such as cancerous cells, in vivo, allowing for the correction of derailed cellular mechanisms.
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