1. Structural Biology Program, Memorial Sloan-Kettering Cancer Center, New York 10021, USA
2. These authors contributed equally to this work

Correspondence to: Dinshaw J. Patel Email: pateld@mskcc.org
Coordinates for the PAZ–siRNA complexes containing 2-nt ribo- and deoxyribonucleotide 3' overhangs have been deposited in the Protein Data Bank under accession codes 1SI3 and 1SI2, respectively.

Abstract

Short RNAs mediate gene silencing, a process associated with virus resistance, developmental control and heterochromatin formation in eukaryotes^{1, 2, 3, 4, 5}. RNA silencing is initiated through Dicer-mediated processing of double-stranded RNA into small interfering RNA (siRNA)^{6, 7}. The siRNA guide strand associates with the Argonaute protein in silencing effector complexes, recognizes complementary sequences and targets them for silencing^{8, 9, 10, 11}. The PAZ domain is an RNA-binding module found in Argonaute and some Dicer proteins and its structure has been determined in the free state^{12, 13, 14}. Here, we report the 2.6 Å crystal structure of the PAZ domain from human Argonaute eIF2c1 bound to both ends of a 9-mer siRNA-like duplex. In a sequence-independent manner, PAZ anchors the 2-nucleotide 3' overhang of the siRNA-like duplex within a highly conserved binding pocket, and secures the duplex by binding the 7-nucleotide phosphodiester backbone of the overhang-containing strand and capping the 5'-terminal residue of the complementary strand. On the basis of the structure and on binding assays, we propose that PAZ might serve as an siRNA-end-binding module for siRNA transfer in the RNA silencing pathway, and as an anchoring site for the 3' end of guide RNA within silencing effector complexes.

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