| Accession: | |
|---|---|
| Functional site class: | ARS2 C-terminal leg domain ligand |
| Functional site description: | ARS2 is a central hub in RNA processing and decay. It is a large modular protein with several well-described interaction surfaces and partners. It forms a stable complex with CBC through its C-terminal disordered tail and interacts with RNA, proteins and multi-subunit complexes. The C-terminal arm is a ZnF domain that can bind RNA and protein partners through adjacent surfaces. It has a positively charged patch on its surface that is bound by diverse protein partners involved in different steps of RNA processing through the acidic EDGEI motif. The interaction is conserved from yeast to human and it enables the mutually exclusive binding of diverse partners to ARS2. |
| ELM Description: | The acidic EDGEI motif is located within disordered regions and binds ARS2 with a low-micromolar affinity (Foucher,2022). It forms an extended U-shaped structure when it binds to the highly conserved lysine and hydrophobic residues on the surface of the ARS2 C-terminal leg domain (7QY5). Triple mutations of the three key lysines in this ZnF domain or to the negative charged residues of the motif abolish the interaction (Schulze,2018; Dobrev,2021; Foucher,2022). Proteins of diverse protein families harbour such a motif often in two or three adjacent copies (Foucher,2022), enabling mutually exclusive binding of different RNA decay/processing/splicing factors to the CBC-ARS2 complex (Schulze,2018). In most proteins the motif is highly conserved among vertebrates, but in some cases also in for example, invertebrates and yeasts (Foucher,2022). Furthermore, the EDGEI-mediated interaction of PHAX with ARS2 seems to be conserved from plants to humans, as the N-terminal EDGEI motif of A. thaliana PHAX is likely to mediate the binding to the plant ARS2 homolog SERRATE (Giacometti,2017). Looking at the alignments of the validated motif instances, glutamic acid is strictly retained in the 1st position, as well as glycine in the 3rd position. Variations between glutamic and aspartic acid occur in the 2nd position. There are patches of conserved negatively charged residues in the flanking regions of the motif, especially in the C-terminal flank, that may contact positively charged residues on the ARS2 surface Aspartic acid in the first position is only seen in the first two motifs of ZC3H18, however it has a third motif “EEGEV” and the motifs have not been individually studied, so the first two might just bind weakly (Rouviere,2023). The only motif with an aspartic acid in the 4th position is that of HnRNPC but it was only seen to bind to ARS2 in one high-throughput assay and the motif was not studied in detail (Schulze,2018). Therefore, we concluded on a stricter motif definition for ELM. |
| Pattern: | E[ED]G[EQ][ILVM].{0,2}[DE] |
| Pattern Probability: | 0.0000092 |
| Present in taxon: | Eukaryota |
| Interaction Domain: |
SERRATE/Ars2, C-terminal (IPR007042)
This domain can be found in the C terminus of the SERRATE (SE) from plants and its homologue, Ars2, from animals
(Stochiometry: 1 : 1)
|
 Abstract |
Eukaryotic genomes are pervasively transcribed (Villa,2023), which can lead to an over-abundance of RNAs. To ensure cell integrity, there are several RNA surveillance, processing and degradation mechanisms that remove specific and aberrant RNAs. Degradation of nuclear RNAs is carried out by the RNA exosome (Zinder,2017). To selectively target RNAs to the nuclease machinery, eukaryotic cells have multi-subunit targeting complexes that direct specific classes of RNAs to the exosome for degradation. In the fission yeast S. pombe, the targeting complex, MTREC, consists of a core complex with the zinc-finger protein, Red1 (Q9UTR8), and an RNA-helicase, Mtl1. This complex is responsible for targeting a variety of classes of mRNAs to the exosome, including meiotic mRNAs (24713849) and unstable and unspliced mRNAs (Zhou,2015). The selection of RNAs is determined by binding of protein sub-modules to the MTREC core complex. Interactions with sub-modules is driven by the multiple interaction surfaces of Red1 (Dobrev,2021). The interaction of Red1 with Ars2 (O94326) is mediated by the Red1 EDGEI motif that recruits the Ars2-Cbc submodule, with cap-binding proteins, Cbc1 (O14253) and Cbc2 (Q9P383). While studied more extensively in humans, this Red1/Mtl1-associated sub-module is thought to be responsible for processing, localization and degradation of RNA polymerase II transcripts containing a 5’ m7G cap. Ars2 contains a C-terminal zinc-finger domain that interacts with the EDGEI motif in Red1. In humans the RNA-binding protein ARS2 (Q9BXP5) has been implicated in transcriptional, post-transcriptional as well as early transcription termination activities. Accordingly, the ARS2-CBC complex interacts with diverse RNA degradation complexes, processing and splicing factors, many of which employ one or more EDGEI motifs to interact with ARS2. Thus, this motif-mediated interaction is conserved from yeast to humans and ensures the mutually exclusive recruitment of distinct RNA-processing machineries to ARS2. The hitherto described ARS2 interactors employing the EDGEI motif include the PolyA tail exosome targeting (PAXT) complex subunit ZFC3H1, the mRNA Transcription-Export (TREX) complex subunit THOC1, the ZC3H18 protein making the link with the Nuclear Exosome Targeting (NEXT) complex, the ZC3H4 restriction factor in transcription termination, splicing factor THRAP3, 3’ end processing factor CPSF2, FLASH, PHAX and the mRNA export factor NCBP3 (Schulze,2018, Foucher,2022; Rouviere,2023). ZC3H6, RTF1 and PRPF4B are also likely to mediate interactions with ARS2 through this motif (Schulze,2018, Foucher,2022). Therefore, EDGEI-motif-mediated interactions have a huge role in the moonlighting potential of the ARS2-CBC complex. The A. thaliana ortholog of ARS2 called SERRATE (Q9ZVD0) was shown to be central in the formation of nuclear miRNA processing dicing bodies through liquid-liquid phase separation (Xie,2021). ARS2 partners often harbouring multiple copies of the EDGEI motif and thus likely mediating multivalent interactions with ARS2 imply that this phenomenon could also be conserved in animals and humans. |
5 selected references:
9 GO-Terms:
21 Instances for LIG_ARS2_EDGEI_1
(click table headers for sorting; Notes column: =Number of Switches, =Number of Interactions)
Please cite:
ELM-the Eukaryotic Linear Motif resource-2024 update.
(PMID:37962385)
ELM data can be downloaded & distributed for non-commercial use according to the ELM Software License Agreement
ELM data can be downloaded & distributed for non-commercial use according to the ELM Software License Agreement