Structural Basis for piRNA 2-O-methylated 3-end Recognition by Piwi PAZ (Piwi/Argonaute/Awille) Domains

Journal Article · Sat Dec 31 04:00:00 EST 2011 · Proceedings of the National Academy of Sciences of the United States of America

DOI:https://doi.org/10.1073/pnas.1017762108· OSTI ID:1041665

Tian, Y; Simanshu, D; Ma, J; Patel, D

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{sub 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{sub 3} and 2'-OH at their 3' ends. These structures explain the molecular basis underlying accommodation of the 2'-OCH{sub 3} group within a preformed Hiwi1 PAZ domain binding pocket, whose hydrophobic characteristics account for the preferential binding of 2'-OCH{sub 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{sub 3} 3' ends.

• Research Organization: BROOKHAVEN NATIONAL LABORATORY (BNL)
• Sponsoring Organization: USDOE SC OFFICE OF SCIENCE (SC)
• DOE Contract Number: AC02-98CH10886
• OSTI ID: 1041665
• Report Number(s): BNL--97343-2012-JA
• Journal Information: Proceedings of the National Academy of Sciences of the United States of America, Journal Name: Proceedings of the National Academy of Sciences of the United States of America Journal Issue: 3 Vol. 108; ISSN PNASA6; ISSN 0027-8424
• Country of Publication: United States
• Language: English

Related Subjects

59 BASIC BIOLOGICAL SCIENCES
60 APPLIED LIFE SCIENCES
DEFECTS
FERTILITY
GAMETOGENESIS
PROTEINS
RNA
TARGETS