Structural insights into the specific recognition of DSR by the YTH domain containing protein Mmi1

Abstract

Meiosis is one of the most dramatic differentiation programs accompanied by a striking change in gene expression profiles in fission yeast Schizosaccharomyces pombe. Whereas a number of meiosis-specific transcripts are expressed untimely in mitotic cells, and the entry of meiosis will be blocked as the accumulation of meiosis-specific mRNAs in the mitotic cells. A YTH domain containing protein Mmi1 was identified as a pivotal effector in a post-transcriptional event termed selective elimination of meiosis-specific mRNAs. Mmi1 can recognize and bind a class of meiosis-specific transcripts expressed inappropriately in mitotic cells, which all contain a conservative region called DSR, as a mark to remove them in cooperation with nuclear exosomes. Here we report the 1.6 Å resolution crystal structure of the Mmi1-YTH domain in complex with a high consensus hexanucleotide motif, which is multiple copied in the DSR region. Our structure observations, supported by site-directed mutations of key residues illustrate the mechanism for specific recognition of DSR-RNA by Mmi1. Moreover, different from other YTH domain family proteins, Mmi1-YTH domain has a distinctive RNA-binding properties although it has a similar fold as other ones.

The YTH Domain Protein ECT2 Is an m6A Reader Required for Normal Trichome Branching in Arabidopsis

“…In S. pombe, the Mmi1 protein carries a YTH domain that unambiguously belongs to the DC group (Figure 1, statistical support of 1) and could (based on this analysis) be considered to be an m 6 A binding motif. Yet, this domain lost this ability in the absence of such an epitranscriptomic mark in fission yeast (Wu et al, 2017). Mmi1 YTH adopts a structural fold highly similar to that of m 6 A binding motifs and displays a putative m 6 A aromatic cage (Touat-Todeschini et al, 2017;Wu et al, 2017).…”

“…Yet, this domain lost this ability in the absence of such an epitranscriptomic mark in fission yeast (Wu et al, 2017). Mmi1 YTH adopts a structural fold highly similar to that of m 6 A binding motifs and displays a putative m 6 A aromatic cage (Touat-Todeschini et al, 2017;Wu et al, 2017). Nevertheless, while bona fide binding cages create a hydrophobic environment to accommodate m 6 A that consists of three amino acids with hydrophobic side chains [W/W/(Y, W, or L)], the S. pombe cage has a positively charged histidine in the third position that is likely to hinder m 6 A binding.…”

YTH-RNA-binding protein prevents deleterious expression of meiotic proteins by tethering their mRNAs to nuclear foci

“…DSR activity is exhibited by enriched repeats of the hexanucleotide UNAAAC motif ( Hiriart et al, 2012 ; Yamashita et al, 2012 ). The Mmi1 YTH domain preferentially binds to the unmethylated UNAAAC motif, contrasting with the YTH domains in other organisms including mammals, which selectively bind to N 6 -methyladenosine-containing RNAs ( Chatterjee et al, 2016 ; Wang et al, 2016 ; Wu et al, 2017 ). The DSR region has been found in a group of meiotic transcripts including mei4, which encodes a key meiotic transcription factor ( Horie et al, 1998 ), and ssm4, which encodes a subunit of the dynactin complex ( Niccoli et al, 2004 ).…”

Meiotic gene silencing complex MTREC/NURS recruits the nuclear exosome to YTH-RNA-binding protein Mmi1

“…Meiotic transcripts are recognized by a YTH family RNA-binding protein, Mmi1, through direct binding of the YTH domain with UNAAAC DSR motifs [3,6]. The mode of Mmi1 interaction with RNAs is different from that of other YTH proteins, and Mmi1 does not recognize N 6 -methyladenosine-containing RNAs [8][9][10][11].…”