Proteopedia

4b9w

Structure of extended Tudor domain TD3 from mouse TDRD1 in complex with MILI peptide containing dimethylarginine 45.Structure of extended Tudor domain TD3 from mouse TDRD1 in complex with MILI peptide containing dimethylarginine 45.

Structural highlights

4b9w is a 4 chain structure with sequence from Lk3 transgenic mice. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:
NonStd Res:
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

[TDRD1_MOUSE] Plays a central role during spermatogenesis by participating in the repression transposable elements and preventing their mobilization, which is essential for the germline integrity. Acts via the piRNA metabolic process, which mediates the repression of transposable elements during meiosis by forming complexes composed of piRNAs and Piwi proteins and governs the methylation and subsequent repression of transposons. Required for the localization of Piwi proteins to the meiotic nuage. Involved in the piRNA metabolic process by ensuring the entry of correct transcripts into the normal piRNA pool and limiting the entry of cellular transcripts into the piRNA pathway. May act by allowing the recruitment of piRNA biogenesis or loading factors that ensure the correct entry of transcripts and piRNAs into Piwi proteins.[1] [2] [3] [PIWL2_MOUSE] Endoribonuclease that plays a central role during spermatogenesis by repressing transposable elements and preventing their mobilization, which is essential for the germline integrity (PubMed:11578866, PubMed:14736746, PubMed:17446352, PubMed:18381894, PubMed:18922463, PubMed:26669262). Plays an essential role in meiotic differentiation of spermatocytes, germ cell differentiation and in self-renewal of spermatogonial stem cells (PubMed:11578866, PubMed:14736746, PubMed:17446352, PubMed:18381894, PubMed:18922463, PubMed:26669262). Its presence in oocytes suggests that it may participate in similar functions during oogenesis in females (PubMed:11578866, PubMed:14736746, PubMed:17446352, PubMed:18381894, PubMed:18922463, PubMed:26669262). Acts via the piRNA metabolic process, which mediates the repression of transposable elements during meiosis by forming complexes composed of piRNAs and Piwi proteins and govern the methylation and subsequent repression of transposons (PubMed:11578866, PubMed:14736746, PubMed:17446352, PubMed:18381894, PubMed:18922463, PubMed:26669262). During piRNA biosynthesis, plays a key role in the piRNA amplification loop, also named ping-pong amplification cycle, by acting as a 'slicer-competent' piRNA endoribonuclease that cleaves primary piRNAs, which are then loaded onto 'slicer-incompetent' PIWIL4 (PubMed:22020280, PubMed:23706823, PubMed:26669262). PIWIL2 slicing produces a pre-miRNA intermediate, which is then processed in mature piRNAs, and as well as a 16 nucleotide by-product that is degraded (PubMed:28633017). Required for PIWIL4/MIWI2 nuclear localization and association with secondary piRNAs antisense (PubMed:18381894, PubMed:18922463, PubMed:26669262). Besides their function in transposable elements repression, piRNAs are probably involved in other processes during meiosis such as translation regulation (PubMed:19114715). Indirectly modulates expression of genes such as PDGFRB, SLC2A1, ITGA6, GJA7, THY1, CD9 and STRA8 (PubMed:16261612).[4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14]

Publication Abstract from PubMed

Piwi-interacting RNAs (piRNAs) are small noncoding RNAs expressed in the germline of animals. They associate with Argonaute proteins of the Piwi subfamily, forming ribonucleoprotein complexes that are involved in maintaining genome integrity. The N-terminal region of some Piwi proteins contains symmetrically dimethylated arginines. This modification is thought to enable recruitment of Tudor domain-containing proteins (TDRDs), which might serve as platforms mediating interactions between various proteins in the piRNA pathway. We measured the binding affinity of the four individual extended Tudor domains (TDs) of murine TDRD1 protein for three different methylarginine-containing peptides from murine Piwi protein MILI. The results show a preference of TD2 and TD3 for consecutive MILI peptides, whereas TD4 and TD1 have, respectively, lower and very weak affinity for any peptide. The affinity of TD1 for methylarginine peptides can be restored by a single-point mutation back to the consensus aromatic cage sequence. These observations were confirmed by pull-down experiments with endogenous Piwi and Piwi-associated proteins. The crystal structure of TD3 bound to a methylated MILI peptide shows an unexpected orientation of the bound peptide, with additional contacts of nonmethylated residues being made outside of the aromatic cage, consistent with solution NMR titration experiments. Finally, the molecular envelope of the four tandem Tudor domains of TDRD1, derived from small angle scattering data, reveals a flexible, elongated shape for the protein. Overall, the results show that TDRD1 can accommodate different peptides from different proteins, and can therefore act as a scaffold protein for complex assembly in the piRNA pathway.

The multiple Tudor domain-containing protein TDRD1 is a molecular scaffold for mouse Piwi proteins and piRNA biogenesis factors.,Mathioudakis N, Palencia A, Kadlec J, Round A, Tripsianes K, Sattler M, Pillai RS, Cusack S RNA. 2012 Sep 20. PMID:22996915[15]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

  1. ↑ Chuma S, Hosokawa M, Kitamura K, Kasai S, Fujioka M, Hiyoshi M, Takamune K, Noce T, Nakatsuji N. Tdrd1/Mtr-1, a tudor-related gene, is essential for male germ-cell differentiation and nuage/germinal granule formation in mice. Proc Natl Acad Sci U S A. 2006 Oct 24;103(43):15894-9. Epub 2006 Oct 12. PMID:17038506 doi:http://dx.doi.org/10.1073/pnas.0601878103
  2. ↑ Reuter M, Chuma S, Tanaka T, Franz T, Stark A, Pillai RS. Loss of the Mili-interacting Tudor domain-containing protein-1 activates transposons and alters the Mili-associated small RNA profile. Nat Struct Mol Biol. 2009 Jun;16(6):639-46. doi: 10.1038/nsmb.1615. Epub 2009 May, 24. PMID:19465913 doi:http://dx.doi.org/10.1038/nsmb.1615
  3. ↑ Vagin VV, Wohlschlegel J, Qu J, Jonsson Z, Huang X, Chuma S, Girard A, Sachidanandam R, Hannon GJ, Aravin AA. Proteomic analysis of murine Piwi proteins reveals a role for arginine methylation in specifying interaction with Tudor family members. Genes Dev. 2009 Aug 1;23(15):1749-62. doi: 10.1101/gad.1814809. Epub 2009 Jul 7. PMID:19584108 doi:http://dx.doi.org/10.1101/gad.1814809
  4. ↑ Kuramochi-Miyagawa S, Kimura T, Yomogida K, Kuroiwa A, Tadokoro Y, Fujita Y, Sato M, Matsuda Y, Nakano T. Two mouse piwi-related genes: miwi and mili. Mech Dev. 2001 Oct;108(1-2):121-33. PMID:11578866
  5. ↑ Kuramochi-Miyagawa S, Kimura T, Ijiri TW, Isobe T, Asada N, Fujita Y, Ikawa M, Iwai N, Okabe M, Deng W, Lin H, Matsuda Y, Nakano T. Mili, a mammalian member of piwi family gene, is essential for spermatogenesis. Development. 2004 Feb;131(4):839-49. doi: 10.1242/dev.00973. Epub 2004 Jan 21. PMID:14736746 doi:http://dx.doi.org/10.1242/dev.00973
  6. ↑ Lee JH, Engel W, Nayernia K. Stem cell protein Piwil2 modulates expression of murine spermatogonial stem cell expressed genes. Mol Reprod Dev. 2006 Feb;73(2):173-9. doi: 10.1002/mrd.20391. PMID:16261612 doi:http://dx.doi.org/10.1002/mrd.20391
  7. ↑ Aravin AA, Sachidanandam R, Girard A, Fejes-Toth K, Hannon GJ. Developmentally regulated piRNA clusters implicate MILI in transposon control. Science. 2007 May 4;316(5825):744-7. doi: 10.1126/science.1142612. Epub 2007 Apr , 19. PMID:17446352 doi:http://dx.doi.org/10.1126/science.1142612
  8. ↑ Kuramochi-Miyagawa S, Watanabe T, Gotoh K, Totoki Y, Toyoda A, Ikawa M, Asada N, Kojima K, Yamaguchi Y, Ijiri TW, Hata K, Li E, Matsuda Y, Kimura T, Okabe M, Sakaki Y, Sasaki H, Nakano T. DNA methylation of retrotransposon genes is regulated by Piwi family members MILI and MIWI2 in murine fetal testes. Genes Dev. 2008 Apr 1;22(7):908-17. doi: 10.1101/gad.1640708. PMID:18381894 doi:http://dx.doi.org/10.1101/gad.1640708
  9. ↑ Aravin AA, Sachidanandam R, Bourc'his D, Schaefer C, Pezic D, Toth KF, Bestor T, Hannon GJ. A piRNA pathway primed by individual transposons is linked to de novo DNA methylation in mice. Mol Cell. 2008 Sep 26;31(6):785-99. doi: 10.1016/j.molcel.2008.09.003. PMID:18922463 doi:http://dx.doi.org/10.1016/j.molcel.2008.09.003
  10. ↑ Unhavaithaya Y, Hao Y, Beyret E, Yin H, Kuramochi-Miyagawa S, Nakano T, Lin H. MILI, a PIWI-interacting RNA-binding protein, is required for germ line stem cell self-renewal and appears to positively regulate translation. J Biol Chem. 2009 Mar 6;284(10):6507-19. Epub 2008 Dec 29. PMID:19114715 doi:http://dx.doi.org/M809104200
  11. ↑ De Fazio S, Bartonicek N, Di Giacomo M, Abreu-Goodger C, Sankar A, Funaya C, Antony C, Moreira PN, Enright AJ, O'Carroll D. The endonuclease activity of Mili fuels piRNA amplification that silences LINE1 elements. Nature. 2011 Oct 23;480(7376):259-63. doi: 10.1038/nature10547. PMID:22020280 doi:http://dx.doi.org/10.1038/nature10547
  12. ↑ Di Giacomo M, Comazzetto S, Saini H, De Fazio S, Carrieri C, Morgan M, Vasiliauskaite L, Benes V, Enright AJ, O'Carroll D. Multiple epigenetic mechanisms and the piRNA pathway enforce LINE1 silencing during adult spermatogenesis. Mol Cell. 2013 May 23;50(4):601-8. doi: 10.1016/j.molcel.2013.04.026. PMID:23706823 doi:http://dx.doi.org/10.1016/j.molcel.2013.04.026
  13. ↑ Yang Z, Chen KM, Pandey RR, Homolka D, Reuter M, Janeiro BK, Sachidanandam R, Fauvarque MO, McCarthy AA, Pillai RS. PIWI Slicing and EXD1 Drive Biogenesis of Nuclear piRNAs from Cytosolic Targets of the Mouse piRNA Pathway. Mol Cell. 2016 Jan 7;61(1):138-52. doi: 10.1016/j.molcel.2015.11.009. Epub 2015, Dec 6. PMID:26669262 doi:http://dx.doi.org/10.1016/j.molcel.2015.11.009
  14. ↑ Wenda JM, Homolka D, Yang Z, Spinelli P, Sachidanandam R, Pandey RR, Pillai RS. Distinct Roles of RNA Helicases MVH and TDRD9 in PIWI Slicing-Triggered Mammalian piRNA Biogenesis and Function. Dev Cell. 2017 Jun 19;41(6):623-637.e9. doi: 10.1016/j.devcel.2017.05.021. PMID:28633017 doi:http://dx.doi.org/10.1016/j.devcel.2017.05.021
  15. ↑ Mathioudakis N, Palencia A, Kadlec J, Round A, Tripsianes K, Sattler M, Pillai RS, Cusack S. The multiple Tudor domain-containing protein TDRD1 is a molecular scaffold for mouse Piwi proteins and piRNA biogenesis factors. RNA. 2012 Sep 20. PMID:22996915 doi:http://dx.doi.org/10.1261/rna.034181.112

4b9w, resolution 2.10Å

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