| Accession: | |
|---|---|
| Functional site class: | Nrd1 CID domain ligand |
| Functional site description: | Noncoding RNAs are targeted by the Nrd1-Nab3-Sen1 (NNS) complex for exosome-dependent degradation. Within the NNS complex Sen1 employs three Nrd1-interacting motifs (NIMs) to bind to the CTD-interacting domain (CID) of Nrd1. The Trf4-Air2-Mtr4 (TRAMP) complex recognizes and polyadenylates the RNAs targeted by the NNS complex for degradation or processing in the exosome. It is formed by a poly(A) polymerase, Trf4 or Trf5, an RNA helicase Mtr4, and an RNA-binding zinc knuckle protein, Air1/2. The Trf4 subunit similarly binds to the CID of Nrd1 by a NIM and thereby stimulates the polyadenylation activity of the TRAMP complex. Besides Trf4, another nuclear exosome cofactor, Mpp6 also interacts with Nrd1 CID through a NIM in a competitive manner. |
| ELM Description: | Based on the known NIM instances, their conservation and structural considerations, NIMs are centred around a strictly conserved Tyr residue that is preceded by some negative charges, especially in the Y-2 position where only Asp, or occasionally Asn, is accepted. The Y-1 position also seems to be restricted to acidic and small residues, while the Y+2 position can only take Pro or Leu (according to mutational studies Ala and Val also (Zhang,2019), but those are not seen in alignments). Similar to the CTD, the residues in the Y+1 to Y+4 positions of NIMs form a β turn when binding to Nrd1 CID. The conserved Y and P/L residues dock into a hydrophobic pocket of CID. The Y also interacts with the P in the Y+2 position via intramolecular stacking and forms an H-bond with the conserved D70 of Nrd1. There are a variable number of acidic residues in the six positions preceding the Y, which bind to a basic patch of CID. Based on the sequences and binding affinities of the instances, it seems that those with Pro in the Y+2 position and/or more acidic residues N-terminal to the Y bind stronger than others (Zhang,2019). Based on the structures of the 3 Sen1 NIMs (6O3W; 6O3X; 6O3Y), accommodating the bulkier Leu at the Y+2 position slightly changes the backbone structure of the motif. In these structures, acidic positions upstream to Y-2 are disordered, contacts with CID were not seen (Zhang,2019). In the Trf4 NIM-Nrd1 CID NMR structure (2MOW), Asp residues in the Y-2 and Y-4 positions contact S25 and R28 of Nrd1, while Glu in the Y-3 and Asp in the Y-6 positions form salt bridges with K30 and K21 of Nrd1 CID, respectively. Interestingly, the NIM motif is remarkably poorly conserved among yeast species compared to other SLiMs. The interaction might have appeared relatively recently in evolution, might be old but got lost in many yeast species, or, if the interaction is found in other species, the motif sequence might evolve very fast, even by the standards of linear motifs. |
| Pattern: | [ED].{0,3}[DN][DEGPA]Y.[PL].. |
| Pattern Probability: | 0.0000422 |
| Present in taxon: | Fungi |
| Interaction Domain: |
CID domain (IPR006569)
The C-terminal domain (CTD) of the large subunit of RNA polymerase II is a
platform for mRNA processing factors and links gene transcription to mRNA
capping, splicing and polyadenylation. CTD recognition is dependent on the
phosphorylation state of the CTD itself, which varies during the course of
transcription but has also been linked to the isomerization state of the CTD's
proline residues. Several RNA-processing factors recognise the CTD by means of
a conserved CTD-interacting domain (CID). Factors with CID domains include the
serine/arginine-rich-like factors SCAF4 and SCAF8, Nrd1 (which is implicated
in polyadenylation-independent RNA 3'-end formation) and Pcf11. Pcf11 is a
conserved and essential subunit of the yeast cleavage factor 1A, which is
required for 3'-RNA processing and transcription termination [, ]. The CID domain is a right-handed superhelix of eight alpha-helices forming a
compact domain. The CID fold closely resembles that of VHS
domains and is related to armadillo-repeat proteins, except for the two amino-terminal helices. Amino acid residues
in the hydrophobic core of the domain are highly conserved across CID domains
[, ].
(Stochiometry: 1 : 1)
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