6oon | pdb_00006oon
Human Argonaute4 bound to guide RNA
Structural highlights
FunctionAGO4_HUMAN Required for RNA-mediated gene silencing (RNAi). Binds to short RNAs such as microRNAs (miRNAs) and represses the translation of mRNAs which are complementary to them. Lacks endonuclease activity and does not appear to cleave target mRNAs. Also required for RNA-directed transcription and replication of the human hapatitis delta virus (HDV).[HAMAP-Rule:MF_03033][1] [2] [3] Publication Abstract from PubMedDespite 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 A 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. Multidomain Convergence of Argonaute during RISC Assembly Correlates with the Formation of Internal Water Clusters.,Park MS, Araya-Secchi R, Brackbill JA, Phan HD, Kehling AC, Abd El-Wahab EW, Dayeh DM, Sotomayor M, Nakanishi K Mol Cell. 2019 Aug 22;75(4):725-740.e6. doi: 10.1016/j.molcel.2019.06.011. Epub, 2019 Jul 16. PMID:31324450[4] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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