Abstract：
:Despite the relevance of Argonaute proteins in RNA silencing, little is known about the structural steps of small RNA loading to form RNA-induced silencing complexes (RISCs). We report the 1.9 Å crystal structure of human Argonaute4 with guide RNA. Comparison with the previously determined apo structure of Neurospora crassa QDE2 revealed that the PIWI domain has two subdomains. Binding of guide RNA fastens the subdomains, thereby rearranging the active-site residues and increasing the affinity for TNRC6 proteins. We also identified two water pockets beneath the nucleic acid-binding channel that appeared to stabilize the mature RISC. Indeed, mutating the water-pocket residues of Argonaute2 and Argonaute4 compromised RISC assembly. Simulations predict that internal water molecules are exchangeable with the bulk solvent but always occupy specific positions at the domain interfaces. These results suggest that after guide RNA-driven conformational changes, water-mediated hydrogen-bonding networks tie together the converged domains to complete the functional RISC structure.
journal_name
Mol Celljournal_title
Molecular cellauthors
Park MS,Araya-Secchi R,Brackbill JA,Phan HD,Kehling AC,Abd El-Wahab EW,Dayeh DM,Sotomayor M,Nakanishi Kdoi
10.1016/j.molcel.2019.06.011subject
Has Abstractpub_date
2019-08-22 00:00:00pages
725-740.e6issue
4eissn
1097-2765issn
1097-4164pii
S1097-2765(19)30444-7journal_volume
75pub_type
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