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Deciphering arginine methylation: Tudor tells the tale

Nature Reviews Molecular Cell Biology volume 12, pages 629–642 (2011)Cite this article

Subjects

Key Points

  • The royal superfamily domains, which include Tudor, chromo, MBT, PWWP and agenet domains, read protein methylation. The Tudor protein family includes a group of proteins that are specialized to recognize arginine methylation, which is an ability that has not been found in other royal superfamily domains.

  • The Tudor family proteins are classified into methylarginine-binding and methyllysine-binding groups. Most methylarginine-binding Tudor proteins are associated with RNA metabolism and most methyllysine-binding Tudor proteins are implicated in chromatin biology.

  • The Tudor domain core contains a conserved β-barrel structure, with an aromatic cage for methyl-ligand recognition. Crystal structures of ligand-bound extended Tudor domains (eTuds) have provided insights into the structural mechanism of methylarginine reading. Tudor domain–methylarginine binding interactions have been implicated in biological processes such as mRNA splicing, small RNA pathways and transciptional regulation.

  • Arginine methylation is an evolutionarily conserved mark on PIWI proteins and is read by the eTuds of the germline Tudor proteins. Methylation-dependent Tudor–PIWI interactions are required for the proper function of the PIWI-interacting RNA (piRNA) pathway.

  • In the animal germ line, genetic studies have revealed that Tudor proteins function as adaptors to facilitate the assembly of nuage and ensure undisrupted gametogenesis.

Abstract

Proteins can be modified by post-translational modifications such as phosphorylation, methylation, acetylation and ubiquitylation, creating binding sites for specific protein domains. Methylation has pivotal roles in the formation of complexes that are involved in cellular regulation, including in the generation of small RNAs. Arginine methylation was discovered half a century ago, but the ability of methylarginine sites to serve as binding motifs for members of the Tudor protein family, and the functional significance of the protein–protein interactions that are mediated by Tudor domains, has only recently been appreciated. Tudor proteins are now known to be present in PIWI complexes, where they are thought to interact with methylated PIWI proteins and regulate the PIWI-interacting RNA (piRNA) pathway in the germ line.

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Figure 1: Structural features of royal superfamily domains and their binding to methylated ligands.
Figure 2: Domain architectures of the human Tudor protein family.
Figure 3: Structure of the extended Tudor domain in complex with methylated peptides.
Figure 4: Germline Tudor proteins and Tudor–PIWI interactions.
Figure 5: Tudor domains as multivalent adaptors.

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Acknowledgements

We dedicate this paper to Maggie Pawson, in memory of her many contributions to the world of signal transduction. We thank J. Park for assistance with the figures and B. Liu, G. Gish and J. Min for comments on the manuscript. C.C. and J.J. are recipients of fellowships from the Canadian Institutes for Health Research (CIHR). Work in the laboratory of T.P. is supported by grants from the CIHR, the Canadian Cancer Society, Genome Canada through the Ontario Genomics Institute and the Ontario Research Fund.

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  1. Samuel Lunenfeld Research Institute, Mount Sinai Hospital, 600 University Avenue, Toronto, M5G 1X5, Ontario, Canada

    Chen Chen, Timothy J. Nott, Jing Jin & Tony Pawson

  2. Department of Molecular Genetics, University of Toronto, Toronto, M5S 1A8, Ontario, Canada

    Tony Pawson

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Supplementary information

41580_2011_BFnrm3185_MOESM1_ESM.pdf

Supplementary information S1 (timeline) | Historical timeline of Tudor domain recognition of arginine methylation. (PDF 256 kb)

41580_2011_BFnrm3185_MOESM2_ESM.pdf

Supplementary information S2 (figure) | Domain architectures of the Tudor domain protein family of human, Drosophila and fission yeast. (PDF 289 kb)

Supplementary information S3 (figure) | Examples of Tudor domain mediated methylarginine binding. (PDF 219 kb)

41580_2011_BFnrm3185_MOESM4_ESM.pdf

Supplementary information S4 (table) | Function of the mammalian TDRD group of Tudor proteins in the germline. (PDF 241 kb)

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DATABASES

Protein Data Bank

1MHN

2IG0

1KNA

2PQW

2X4X

2BKD

3OMC

3NTH

FURTHER INFORMATION

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Glossary

Chromo

A royal superfamily domain of ∼50 amino acids that is best known for binding to methylated lysine on histone tails.

MBT

A royal superfamily domain that binds to methylated lysine.

PWWP

A royal superfamily domain that contains a PWWP signature motif. Some PWWP domains bind methylated lysine.

Plant agenet

A Tudor-like domain that was discovered in plants and named after the Plantagenet dynasty of English monarchs. This royal superfamily domain is also present in animal proteins such as fragile X mental retardation protein (FMRP) and its autosomal paralogues fragile X mental retardation syndrome-related protein 1 (FXR1) and FXR2.

Transposon

A mobile DNA element that can translocate in the genome. Transposons are considered as parasitic DNA elements of the host genome and can be classified based on the mechanism of transposition as retrotransposons (copy and paste) and DNA transposons (cut and paste).

Plant homeodomain

(PHD). PHD domains are conserved zinc-finger domains that are found in many nuclear proteins involved in chromatin remodelling and bind methylated lysines on histone tails.

WD40

A protein motif of ∼40 amino acids that usually ends with a WD dipeptide. Repeated WD40 motifs fold into a circular β-propeller structure that mediates protein–protein interactions.

K homology

(KH). A protein fold of ∼70 amino acids that was first identified in heterologous nuclear ribonucleoprotein K (HNRNPK). KH domains bind RNA or single-stranded DNA and are present in a wide array of nucleic acid-binding proteins.

Staphylococcal nuclease-like

(SN-like). The SN-like domain is implicated in single-stranded nucleic acid-binding and is present as four intact repeats in SN-like domain containing protein 1(SND1).

Cation–π interactions

Noncovalent electrostatic interactions between an electron-rich π system (for example, in an aromatic ring) and a cation.

Small nuclear ribonucleoprotein

(snRNP). RNA–protein complexes that are components of the spliceosome, which is the precursor mRNA splicing apparatus found in eukaryotic nuclei.

Polar granules

Maternally produced cytoplasmic granules localized at the posterior end of a Drosophila melanogaster early embryo and oocyte. These granules are required for germ cell formation.

Nuage

A perinuclear, electron-dense, cloud-like structure first identified in Drosophila melanogaster ovarian nurse cells. It is used as a general term for germ granules, which are cytoplasmic, non-membranous, ribonucleoprotein organelles that are found in animal germ cells.

Long interspersed nuclear elements

(LINEs). A family of autonomous non-long terminal repeat (non-LTR) retrotransposons that mobilize by retrotransposition. They are one of the most abundant groups of retrotransposons in the human genome.

Pi-body

Pi-bodies are intermitochondrial cement-like, cytoplasmic germ granules that are found in mammalian fetal spermatogonia. The proteins that are found in the pi-body include several PIWI-interacting RNA pathway proteins such as TDRD1 (Tudor domain-containing protein 1), MILI, Vasa, GASZ (germ cell-specific ankyrin, SAM and basic leucine zipper domain-containing protein) and MOV10L1 (moloney leukaemia virus 10-like protein 1).

PiP-body

Processing body (P-body)-like bodies are cytoplasmic germ granules in fetal spermatogonia that are distinct from pi-bodies. PiP-bodies contain PIWI-interacting RNA pathway components such as MIWI2, Tudor-domain containing protein 9 (TDRD9), Maelstrom (MAEL) and Vasa, and also processing-body markers such as GW182, mRNA-decapping enzyme 1A (DCP1A), 5–3′ exoribonuclease 1 (XRN1) and DEAD box protein 6 (DDX6).

Chromatoid body

A prominent perinuclear electron-dense germ granule in male postmeiotic round spermatids. It is enriched with RNA and protein components of the PIWI-interacting RNA pathway as well as those of the microRNA pathway.

Lotus domain

(Also known as an OST-HTH domain). A conserved protein fold of ∼90 amino acids that is present in several germline- specific proteins, including Linkman, Oskar and Tudor domain-containing protein 5 (TDRD5) and TDRD7. The lotus domain is speculated to bind RNA.

RNA recognition motif

(RRM). A protein fold of ∼90 amino acids with putative RNA-binding properties that is present in many RNA-binding proteins.

Intermitochondrial cement

An electron-dense cementing material that is associated with mitochondria in mammalian spermatocytes and spermatogonia.

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Chen, C., Nott, T., Jin, J. et al. Deciphering arginine methylation: Tudor tells the tale. Nat Rev Mol Cell Biol 12, 629–642 (2011). https://doi.org/10.1038/nrm3185

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