Structural basis for recognition of arginine methylated Piwi proteins by the extended Tudor domain

Abstract

Arginine methylation modulates diverse cellular processes and represents a molecular signature of germ-line-specific Piwi family proteins. A subset of Tudor domains recognize arginine methylation modifications, but the binding mechanism has been lacking. Here we establish that, like other germ-line Tudor proteins, the ancestral staphylococcal nuclease domain-containing 1 (SND1) polypeptide is expressed and associates with PIWIL1/Miwi in germ cells. We find that human SND1 binds PIWIL1 in an arginine methylation-dependent manner with a preference for symmetrically dimethylated arginine. The entire Tudor domain and a bifurcated SN domain are required for this binding activity, whereas the canonical Tudor domain alone is insufficient for methylarginine ligand binding. Crystal structures show that the intact SND1 extended Tudor domain forms a wide and negatively charged binding groove, which can accommodate distinct symmetrically dimethylated arginine peptides from PIWIL1 in different orientations. This analysis explains how SND1 preferentially recognizes symmetrical dimethylarginine via an aromatic cage and conserved hydrogen bonds, and provides a general paradigm for the binding mechanisms of methylargininecontaining peptides by extended Tudor domains.Piwi-interacting RNA | Tudor domain-containing proteins

Clipping of arginine-methylated histone tails by JMJD5 and JMJD7

“…40), but is more than one order of magnitude higher than affinities between Tudor domains and methylated arginines (∼4 μM; ref. 41). This is also true compared with pH3K4me2, where the binding affinity between c-JMJD5 and pH3K4me2 is ∼4 μM (Fig.…”

The multiple Tudor domain-containing protein TDRD1 is a molecular scaffold for mouse Piwi proteins and piRNA biogenesis factors

“…Only recently have the NMR structures of the minimal, prototypical Tudor domains of SMN and SPF30 (survival of motor neuron-related splicing factor 30) been determined in complex with single symmetrically and asymmetrically dimethylated arginine residues. The second group comprises so-called Tudor domain-containing (TDRD) proteins and is represented by the Drosophila TUDOR (Liu et al 2010a) or the human Staphylococcal nuclease domaincontaining 1 (SND1) (Liu et al 2010b). These proteins contain one or more extended Tudor domains (eTud), typically of z180 residues, in which the prototypic Tudor module is fused to a staphylococcal nuclease (SN) domain.…”

Tudor staphylococcal nuclease: biochemistry and functions

“…33 The interaction with PIWIL1/Miwi, a specific member of the Argonaute family, suggests a role for TSN in the biogenesis of noncoding RNAs in mammals. 25,34 Because of the cross-kingdom conservation of TSN sequence and its molecular structure, this protein might perform similar functions in different organisms. Indeed, both animal and plant TSN proteins interact with several SGassociated proteins 11,12,35,36 and control the fate (stabilization or degradation) of specific mRNAs during stress.…”

“…23 This domain has been reported to recognize and bind methylated lysine and arginine of target proteins, which is a key factor for their ability to facilitate the assembly of larger protein complexes at discrete cellular compartments. [24][25][26][27][28][29] It seems that a common function of proteins containing Tudor domain, including TSN, is to act as an adaptor in order to link methylated arginine or lysine to effector molecules with specific catalytic activities. 24 It has recently been shown that human TSN interacts through its Tudor domain with core components of RNA splicing machinery, including Prp8 (human U5-220 kD Protein), two Sm proteins, SmB and SmD1/D3 and the splicing factor SAM68 (Src-associated in mitosis of 68 kDa).…”