title: Structural basis for piRNA 2'-O-methylated 3'-end recognition by Piwi PAZ (Piwi/Argonaute/Zwille) domains.
abstract: Argonaute and Piwi proteins are key players in the RNA silencing pathway, with the former interacting with micro-RNAs (miRNAs) and siRNAs, whereas the latter targets piwi-interacting RNAs (piRNAs) that are 2'-O-methylated (2(')-OCH(3)) at their 3' ends. Germline-specific piRNAs and Piwi proteins play a critical role in genome defense against transposable elements, thereby protecting the genome against transposon-induced defects in gametogenesis and fertility. Humans contain four Piwi family proteins designated Hiwi1, Hiwi2, Hiwi3, and Hili. We report on the structures of Hili-PAZ (Piwi/Argonaute/Zwille) domain in the free state and Hiwi1 PAZ domain bound to self-complementary 14-mer RNAs (12-bp + 2-nt overhang) containing 2(')-OCH(3) and 2'-OH at their 3' ends. These structures explain the molecular basis underlying accommodation of the 2(')-OCH(3) group within a preformed Hiwi1 PAZ domain binding pocket, whose hydrophobic characteristics account for the preferential binding of 2(')-OCH(3) over 2'-OH 3' ends. These results contrast with the more restricted binding pocket for the human Ago1 PAZ domain, which exhibits a reverse order, with preferential binding of 2'-OH over 2(')-OCH(3) 3' ends.
authors.affiliation: Structural Biology Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Tian
authors.forename: Dhirendra K
authors.initials: DK
authors.lastname: Simanshu
authors.forename: Jin-Biao
authors.initials: JB
authors.lastname: Ma
authors.forename: Dinshaw J
authors.initials: DJ
authors.lastname: Patel
mesh_terms: D060565:Argonaute Proteins; D001665:Binding Sites / Q000235:genetics; D003461:Crystallography; D017931:DNA Primers / Q000235:genetics; D039642:Eukaryotic Initiation Factors / Q000235:genetics* / Q000378:metabolism; D008958:Models, Molecular; D017434:Protein Structure, Tertiary; D011506:Proteins / Q000235:genetics* / Q000378:metabolism / Q000648:ultrastructure*; D034622:RNA Interference / Q000502:physiology*; D034741:RNA, Small Interfering / Q000235:genetics*
chemical_list: C115848:AGO1 protein, human; D060565:Argonaute Proteins; D017931:DNA Primers; D039642:Eukaryotic Initiation Factors; C421088:PIWIL1 protein, human; D011506:Proteins; D034741:RNA, Small Interfering