Proc Natl Acad Sci U S A. 2017 Nov 21;114(47):12483-12488. doi: 10.1073/pnas.1711486114. Epub 2017 Nov 8.

Structural basis for arginine methylation-independent recognition of PIWIL1 by TDRD2.

Zhang H¹, Liu K¹, Izumi N², Huang H³, Ding D⁴, Ni Z⁵, Sidhu SS³, Chen C⁴, Tomari Y^6,⁷, Min J^8,⁹.

Author information

1: Structural Genomics Consortium, University of Toronto, Toronto, ON M5G 1L7, Canada.
2: Institute of Molecular and Cellular Biosciences, The University of Tokyo, Tokyo 113-0032, Japan.
3: The Donnelly Centre, University of Toronto, Toronto, ON M5S 3E1, Canada.
4: Department of Animal Science, Michigan State University, East Lansing, MI 48824.
5: Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada.
6: Institute of Molecular and Cellular Biosciences, The University of Tokyo, Tokyo 113-0032, Japan; tomari@iam.u-tokyo.ac.jp jr.min@utoronto.ca.
7: Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Tokyo 113-0032, Japan.
8: Structural Genomics Consortium, University of Toronto, Toronto, ON M5G 1L7, Canada; tomari@iam.u-tokyo.ac.jp jr.min@utoronto.ca.
9: Department of Physiology, University of Toronto, Toronto, ON M5S 1A8, Canada.

Abstract

The P-element-induced wimpy testis (PIWI)-interacting RNA (piRNA) pathway plays a central role in transposon silencing and genome protection in the animal germline. A family of Tudor domain proteins regulates the piRNA pathway through direct Tudor domain-PIWI interactions. Tudor domains are known to fulfill this function by binding to methylated PIWI proteins in an arginine methylation-dependent manner. Here, we report a mechanism of methylation-independent Tudor domain-PIWI interaction. Unlike most other Tudor domains, the extended Tudor domain of mammalian Tudor domain-containing protein 2 (TDRD2) preferentially recognizes an unmethylated arginine-rich sequence from PIWI-like protein 1 (PIWIL1). Structural studies reveal an unexpected Tudor domain-binding mode for the PIWIL1 sequence in which the interface of Tudor and staphylococcal nuclease domains is primarily responsible for PIWIL1 peptide recognition. Mutations disrupting the TDRD2-PIWIL1 interaction compromise piRNA maturation via 3'-end trimming in vitro. Our work presented here reveals the molecular divergence of the interactions between different Tudor domain proteins and PIWI proteins.