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Structural Insights Into the Sequence-Specific Recognition of Piwi by Drosophila Papi

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Structural Insights Into the Sequence-Specific Recognition of Piwi by Drosophila Papi Structural insights into the sequence-specific recognition of Piwi by Drosophila Papi Yuhan Zhanga,b,c, Weiwei Liud, Ronghong Lia,b, Jiaqi Gud,e, Ping Wuc,f, Chao Pengc,f, Jinbiao Mae, Ligang Wua,b, Yang Yud,f, and Ying Huanga,b,c,1 aState Key Laboratory of Molecular Biology, Shanghai Key Laboratory of Molecular Andrology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, Shanghai 200031, China; bUniversity of Chinese Academy of Sciences, Beijing 100049, China; cShanghai Science Research Center, Chinese Academy of Sciences, Shanghai 201204, China; dKey Laboratory of RNA Biology, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China; eState Key Laboratory of Genetic Engineering, Collaborative Innovation Center for Genetics and Development, Department of Biochemistry, School of Life Sciences, Fudan University, Shanghai 200438, China; and fNational Facility for Protein Science in Shanghai, Zhangjiang Laboratory, Shanghai 201210, China Edited by Leemor Joshua-Tor, Howard Hughes Medical Institute and Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, and approved February 16, 2018 (received for review September 29, 2017) The Tudor domain-containing (Tdrd) family proteins play a critical Aubergine (Aub), and Ago3 (13–15). In Drosophila ovaries, the role in transposon silencing in animal gonads by recognizing the precursor piRNAs (prepiRNAs) that are transcribed from piRNA symmetrically dimethylated arginine (sDMA) on the (G/A)R motif clusters are exported to the nuage in the cytoplasm, where the of the N-terminal of PIWI family proteins via the eTud domains. prepiRNAs are cleaved into piRNA intermediates by a mito- ′ Papi, also known as “Tdrd2,” is involved in Zucchini-mediated PIWI- chondrial outer membrane protein Zucchini (Zuc), followed by 3 - ′ end trimming and methylation to yield mature piRNAs (12, interacting RNA (piRNA) 3 -end maturation. Intriguingly, a recent – study showed that, in papi mutant flies, only Piwi-bound piRNAs 16 20). Subsequently, the mature piRNAs are loaded into PIWI increased in length, and not Ago3-bound or Aub-bound piRNAs. proteins to form various piRISCs. Piwi-piRISCs enter the nucleus However, the molecular and structural basis of the Papi–Piwi complex to silence the transposons. Alternatively, mature piRNAs can also be loaded into Aub to trigger the ping-pong cycle that cleaves both is still not fully understood, which limits mechanistic understanding of the transposon mRNAs and the piRNA transcripts (21, 22). the function of Papi in piRNA biogenesis. In the present study, we The Tudor domain-containing (Tdrd) proteins, which are con- determined the crystal structures of Papi-eTud in the apo form and served among flies, worms, and mammals, play important roles in complex with a peptide containing unmethylated or dimethylated in PIWI localization and function through recognizing the R10 residues. Structural and biochemical analysis showed that the sDMA-modified PIWI proteins by eTud domains (2, 15, 23). Papi interaction region on the Drosophila Piwi contains an RGRRR Silkworm Qin and Spn-E, also named “Tdrd4” and “Tdrd9,” motif (R7–R11) distinct from the consensus (G/A)R motif recognized take part in this ping-pong pattern, facilitating the loading of by canonical eTud. Mass spectrometry results indicated that Piwi is piRNAs to Siwi (the silkworm Aub) (24, 25). Mutations in the major binding partner of Papi in vivo. The papi mutant flies Drosophila Qin cause homotypic Aub:Aub interactions instead of suffered from both fertility and transposon-silencing defects, sup- the normal Aub:Ago heterotypic ping-pong interactions (26). porting the important role conferred to Papi in piRNA 3′ processing Tejas (Tej), also called “Tdrd5,” interacts with the RNA helicase through direct interaction with Piwi proteins. Vasa to regulate the localization of some piRNA effectors, such as Papi | Piwi | eTud domain | piRNA biogenesis | 3′-end trimming Significance he Tudor domain was first identified in the Drosophila Tudor In this study, we identified the direct interaction region between T(Tud) protein, which plays an important role in germ cell Drosophila Piwi and Papi. We further determined the crystal formation during oogenesis (1). The core of the Tudor do- structures of Papi-eTud in the apo form, in complex with unme- main adopts an oligonucleotide/oligosaccharide-binding (OB) fold, thylated Piwi peptide, and in complex with symmetrically dime- which is a β-barrel formed by four anti-parallel β-strands (2). A thylated Piwi peptide at arginine-10, which demonstrated that conservedaromaticcageisusuallylocatedonthesurfacetoac- Papi interacts with an RGRRR motif on the N terminus of Piwi in a commodate the methylated ligands. According to the bound li- sequence-specific manner both in vitro and in vivo. This recogni- gands, the Tudor domains are classified into two major groups: a tion sequence, which determines the specificity of Papi–Piwi in- methyllysine-binding group and an arginine-binding group (2, 3). teractions, is different from all previously reported (G/A)R repeats. Tudor domains that recognize methyllysine usually act as histone Our studies provide mechanistic insights into the important role of readers in chromatin biology (4). However, Tudor domains that Papi–Piwi interactions in the 3′ end-trimming process of PIWI- bind methylated arginine are usually involved in RNA processing interacting RNA biogenesis and facilitate the identification of new such as splicing regulation and piRNA (PIWI-interacting RNA)- PIWI-interacting partners of Tudor domain-containing proteins. mediated biogenesis (5). For example, the Tudor domain of spinal Author contributions: J.M., L.W., Y.Y., and Y.H. designed research; Y.Z., W.L., J.G., and muscular atrophy disease protein SMN could bind symmetrically P.W. performed research; Y.Z., R.L., P.W., C.P., and L.W. analyzed data; J.M. contributed dimethylated arginine (sDMA) residues of spliceosome compo- new reagents/analytic tools; and J.M., Y.Y., and Y.H. wrote the paper. nent Sm proteins (6). Moreover, in the piRNA pathway, Tudor The authors declare no conflict of interest. domains hybridized with the staphylococcal nuclease (SN) domain, This article is a PNAS Direct Submission. “ ” “ ” designated as extended-Tudor (eTud) or Tudor-sn domains, Published under the PNAS license. were reported to regulate transposon silencing in the germ cells – Data deposition: Structural coordinates have been deposited in the Protein Data Bank through recognizing the N terminus of PIWI (P-element induced (PDB) database [PDB ID codes 5YGC (Papi-eTud apo), 5YGB (Papi-eTud-D287A), 5YGD wimpy testis) proteins with sDMA modification (7, 8). (Papi-eTud-D287A–Piwi-R10me2s complex), and 5YGF (Papi-eTud-D287A–Piwi- PIWI proteins are a clade of evolutionarily conserved Argonaute unme complex)]. family proteins usually found in animal gonads (9, 10). PIWI pro- 1To whom correspondence should be addressed. Email: [email protected]. teins can interact with piRNAs to form a piRNA-induced silencing This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. complex (piRISC complex) to silence transposons (11–13). There 1073/pnas.1717116115/-/DCSupplemental. are three PIWI proteins in Drosophila melanogaster, namely Piwi, Published online March 12, 2018. 3374–3379 | PNAS | March 27, 2018 | vol. 115 | no. 13 www.pnas.org/cgi/doi/10.1073/pnas.1717116115 Spn-E, Aub, Ago, Krimper, and Maelstrom, to nuage and engages A C in the formation of nuage for piRNA production (27). Recent studies have shown that silkworm Papi (partner of PIWIs/Tdrd2, also known as “BmPapi”) recruits PNLDC1, a PARN family 3′–5′ exoribonuclease, to trim the 3′ end of the piRNA intermediates produced by Zuc cleavage for piRNA maturation (28, 29). Moreover, depletion of TDRKH (the mouse Papi homolog) re- sults in an obvious 3′-end extension of piRNAs and male sterility (28, 30). Similarly, in Drosophila, Papi may be involved in primary piRNA production. Zuc-mediated cleavage of prepiRNA directly generates mature piRNA, while prepiRNAs released from the ping-pong cycle require further resection by Nibbler, which belongs to another 3′–5′ exoribonuclease family (31, 32). The depletion of B Papi increases the length of Piwi-bound piRNA somewhat, leaving both Aub-bound and Ago3-bound piRNAs unaffected (31). D However, the molecular mechanism underlying the function of the Papi–Piwi complex remains unclear. Here, we identified the region of Piwi that interacts with the eTud of Papi. We then determined the crystal structures of Papi-eTud both in the apo form and in complex with unmethylated Piwi (Piwi-unme) or symmetrically dimethylated Piwi at arginine-10 (Piwi-R10me2s). Our structural and biochemical data showed that, unlike the consensus eTud recognition (G/A)R motif, Papi recognizes the RGRRR motif of Piwi in a sequence-specific manner both in vitro and in vivo. Fig. 1. Papi binds to the 14 N-terminal amino acids of Piwi via its eTud domain. Moreover, deletion of papi results in fly fertility defects. In vivo fly (A and B) Co-IP assays to map the interaction regions between Papi and Piwi in rescue experiments further establish that the binding pocket of S2 cells. Domain architectures of Papi and Piwi are schematically presented. (A) Papi is required for its function in fertility and transposon silencing, Co-IP of Myc-tagged wild-type Piwi or truncations with Flag-Papi. (B)Co-IPof in accordance with the structural and biochemical analysis. Our Flag-tagged wild-type Papi or truncations with Myc-Piwi. (C, Upper) The sequence of 94 N-terminal amino acids of Piwi. R-rich clusters are shown in red boxes. findings provide important insight into the role of the interactions BIOCHEMISTRY between Papi and Piwi in piRNA maturation, supporting the re- (Middle) Red lines strike out Rs replaced by As. (Bottom) The wild type and Piwi-N cent discovery that after Zuc cleavage Papi-assisted piRNA trim- mutants were used in GST pull-down assays to check the interactions with GST- ming is consistent with its role in silkworms and mice (28, 30).
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