Argonaute: Difference between revisions
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The Argonaute protein is | <StructureSection load='4ola' size='350' side='right' scene='51/512703/Cv/1' caption='X-ray structure of the entire human Argonaute2 protein complex with RNA (red) (PDB [[4ola]]) at 2.3Å resolution'> | ||
==Function== | |||
The '''Argonaute''' protein is a component of the RISC complex, central to the [[RNA_Interference|RNA-induced silencing]] in eukaryotic organisms <ref name='ref1'>pmid 22539551</ref>. It is found in all higher eukaryotes and it plays an important role in a variety of processes as diverse as embryonic development, cell diferentiation and transposon silencing. These proteins are evolutionarily conserved and can be divided in three subfamilies: Ago, Piwi and Wago. The first are ubiquitously expressed and interact with siRNAs or miRNAs to participate in post-transcriptional gene silencing, both by destabilizing mRNA or by repressing the translation event. Piwi proteins are generally restricted to the germ line and associate piRNAs to mediate silencing of mobile genetic elements <ref name='ref2'>pmid 18304383</ref>. The third and final subclass, Wago, are worm specific. For more details see [[RNA Interference]]. | |||
*'''Argonaute 2''' is called '''slicer''' and is required for the degradation of MicroRNA molecules<ref>pmid 24263100</ref>. | |||
*'''Argonaute 4''' is involved in human RNA-dependent DNA methylation<ref>pmid 31333722</ref>. | |||
*'''Argonaute 10''' is involved in the degradation of MicroRNA molecules<ref>pmid 33571183</ref>. | |||
==Structural Organisation== | ==Structural Organisation== | ||
There are two main structural features common to all Argonaute proteins: the Paz domain and the PIWI domain. Other structural features include the N domain and the Mid domain. | |||
There are two main structural features common to all Argonaute proteins: the | |||
===Paz Domain=== | ===Paz Domain=== | ||
The <scene name='Argonaute/Ago2-paz/1'>Paz Domain</scene> is responsible for binding to the 3'-end overhangs of single-stranded RNAs and siRNA duplexes <ref name='ref3'>pmid 15152257</ref> and was shown to be essential for RISC activation <ref name=' | The <scene name='Argonaute/Ago2-paz/1'>Paz Domain</scene> is responsible for binding to the 3'-end overhangs of single-stranded RNAs and siRNA duplexes <ref name='ref3'>pmid 15152257</ref> and was shown to be essential for RISC activation <ref name='ref4'>pmid 22795694</ref>. <scene name='Argonaute/Ago2-paz-obfold/2'>The domain is composed of two subdomains:</scene> the first is similar to the OB fold, a well known nucleic acid binding fold; the second subdomain is composed of a beta-hairpin followed by an alpha-helix. The cleft in between these two subdomains appears to interact with the 3' ends of ssRNA <ref name='ref5'>pmid 14615801</ref> (<scene name='Argonaute/Ago2-paz-binding-cleft/2'>See in structure</scene>) | ||
===Piwi Domain=== | ===Piwi Domain=== | ||
<scene name='Argonaute/Ago2-piwi/1'>The larger Piwi domain</scene> (~300 aminoacids) is found in a large number of related nucleic-acid binding proteins, in particular those involved in RNA binding and cleavage. In the Argonaute protein, its function is the dsRNA guided hydrolysis of ssRNA <ref name='ref6'>pmid 15800637</ref>. PIWI is structurally an RNase H domain, and in Argonaute it servers as the 'Slicer', or the component responsible for cleaving the mRNA in the RISC complex <ref name='ref7'>pmid 15284453</ref>. Predictions point to <scene name='Argonaute/Ago2-piwi-mg/1'>a putative binding site</scene> for magnesium bivalent cations. However, in contrast to the findings in prokaryotic enzymes, eukaryotic structures were found lacking the metal <ref name='ref1'/>. | |||
===RNA binding regions=== | |||
The majority of the RNA binding residues are located in the PIWI domain. The RNA molecule is bound in a conformation similar to DNA molecules in prokaryotic structures. The fact that the RNA bases 1 to 7 are well-defined in the electron density map hint at an uniform conformation of this region, perhaps forced by the protein. <scene name='Argonaute/Ago2-y529/5'>The 5' base of the RNA molecule interacts</scene> with Y529 through base-stacking, along with hydrogen bonds to this same tyrosine residue, K533, N545 and K566. <scene name='Argonaute/Ago2-water/4'>Water mediates a couple of hydrogen bonds</scene> between the 5' phosphate and K570, R812 and the carboxyl group of A859. As such, the majority of the interactions between Argonaute and the RNA molecule are electrostatic in nature, arising from hydrogen bonding and salt bridges to the phosphate backbone. Van der Waals interactions between the ribose sugar ring and protein residues also contribute to the overall stabilization of the interaction. Residues S220, R357, R714 and R761 of the MID domain, together with a part of the PIWI domain bind the bases 7-9 <ref name='ref1'/>. | |||
== 3D Structures of argonaute == | |||
[[Argonaute 3D structures]] | |||
</StructureSection> | </StructureSection> | ||
==External Resources== | |||
[http://www.uniprot.org/uniprot/Q9UKV8 Uniprot: Q9UKV8] | |||
[http://en.wikipedia.org/wiki/Piwi Wikipedia: Piwi Proteins] | |||
[http://en.wikipedia.org/wiki/Argonaute Wikipedia: Argonaute Proteins] | |||
[http://www.nature.com/nrg/multimedia/rnai/animation/index.html Animation showing the function of Argonaute during RNA interference] | |||
==References== | ==References== | ||
<references/> | <references/> | ||
[[Category:Topic Page]] | |||