The Eukaryotic Linear Motif resource for
Functional Sites in Proteins
Accession:
Functional site class:
Mtr4-Trf4-interaction site
Functional site description:
The TRAMP complex is involved in exosome-mediated degradation of aberrant RNAs and RNA surveillance in the nucleus. Oligo-adenylated tails are added to aberrant RNA substrates, thus marking them for degradation. In Fungi, it is formed by a RNA Helicase, Mtr4, in addition with a poly(A)polymerase, Trf4 or Trf5 and a RNA-binding zinc knuckle protein, Air1/2. The non-covalent binding of Trf4 and Mtr4 is mediated via a short motif, which interacts with the DExH core of Mtr4. The motif is conserved in Fungi.
ELMs with same func. site: LIG_Mtr4_Trf4_1  LIG_Mtr4_Trf4_2 
ELM Description:
The poly(A) polymerase PAPD5 (Q8NDF8) binds to the DExH core (PF00270) of SKIV2L2 (P42285) via a short motif. Compared to the motif conserved in Fungi (LIG_Mtr4_Trf4_1), the core motif sequence slightly changed from DFI in Fungi to DFL (isoleucine I is also accepted instead of leucine) in Vertebrata. Fitting the motif to Vertebrata only, one can derive an altered regular expression pattern Q[RGQ]DF[LI][PS]L[DE][TA]{2}N{5}. Two positions upstream of the core motif a glutamine is conserved, followed by a more flexible position where arginine is most common but glycine and glutamine occur as well. Downstream of the core motif sequence (the core motif sequence seemingly is conserved from the motif in yeast), the sequence allows few substitutions. The first position downstream is either a proline or a serine, followed by a mandatory leucine. Next, a negatively charged amino acid, aspartic acid or glutamic acid follows. In contrast to the motif in yeast, there is no longer a sequence of negatively charged amino acids. Instead, after one or two amino acids where at least one amino acid has to be threonine one finds an arginine-rich region. There is frequently a stretch of five asparagine amino acids. However, the occurrence of overall at least three asparagine amino acids within the range of five amino acids positions seems sufficient.
Note that there is currently no experimental evidence for this motif in Vertebrata. The motif was predicted by sequence alignments by researchers (Losh,2015) and by the curator.
Pattern: Q[RGQ]DF[LI][PS]L[DE]
Pattern Probability: 2.036e-09
Present in taxon: Vertebrata
Interaction Domain:
DEAD (PF00270) DEAD/DEAH box helicase (Stochiometry: 1 : 1)
o See 3 Instances for LIG_Mtr4_Trf4_2
o Abstract
RNA processing and surveillance is a mechanisms closely regulated. In general, RNAs are degraded when their function and use is completed, which means the lifetime of a RNA molecule depends on its type (e.g. long life time for rRNA; short for aberrant RNA). There are several possible pathways for the decay of RNA substrates; one of the major players for degradation and trimming in the nucleus is the exosome (Houseley,2009). Several cofactors (such as the TRAMP complex) are needed by the exosome for target recognition. The TRAMP complex consists of a RNA helicase (MTR4), a poly(A)polymerase (Trf4 or Trf5) and a RNA-binding zinc knuckle protein (Air1 or Air2). While Air1 or Air2 recognizes the RNA substrates, Mtr4 is responsible for unwinding the RNA in order for Trf4 or Trf5 to polyadenylate the substrate (LaCava,2005). This poly(A) tail can be recognized by the exosome, initiating the degradation of the substrate (Hamill,2010). The broad spectrum of possible RNA substrates for TRAMP consists of hypomodified or incorrectly folded tRNA, rRNA, snRNA and snoRNA, incorrectly folded or spliced pre-mRNA, cryptic unstable transcripts (CUTs) and defective pre-ribosomes (Wlotzka,2011, Kadaba,2004, Carneiro,2007, Houseley,2009). Interestingly, the polyadenylation of stable mRNA by the canonical poly(A) polymerase PAP1 does not lead to degradation. The two pathways of modification therefore must be distinguishable. The length of the tail seems to be one way of encoding the addressed pathway. While the polyadenylation added by Trf4/5 is in a range of 10-50 nucleotides, PAP1 adds tails of 60-80 nucleotides (reviewed in Schmidt,2013). Furthermore, Mtr4 can modulate the activity of Trf4/5 in the TRAMP complex, resulting in a poly(A) tail length of only 3-5 nucleotides (Jia,2011).
The duplication of the polymerase Trf and the zinc knuckle protein Air arose due to a whole genome duplication event in Saccharomyces cerevisiae (15004568). The non-covalent binding of Trf4 (P53632) and the DExH-helicase core of Mtr4 (P47047, PF00270) is mediated by the described motif, which is conserved in both Trf4 (P53632) and Trf5 (P48561) in Fungi. In Vertebrata, the motif for interaction between Mtr4 and PAPD5 (human homolog of Trf5 (Houseley,2009)) slightly changed. Interestingly, the motif occurs only on human PAPD5 but not on human PAPD7 or POLS (human homolog of Trf4 Houseley,2009). The potential motif in Vertebrata (proposed through multiple sequence alignment in Losh,2015 and investigated by curator based on alignments) is described in the entry (LIG_MTR4_TRF4_2). However, note that there is no experimental evidence for this motif in Vertebrata yet.
o 6 selected references:

o 9 GO-Terms:

o 3 Instances for LIG_Mtr4_Trf4_2
(click table headers for sorting; Notes column: =Number of Switches, =Number of Interactions)
Acc., Gene-, NameStartEndSubsequenceLogic#Ev.OrganismNotes
W5LIB7 PAPD5
W5LIB7_ASTMX
94 101 DCDVVDQRDFIPLEAANNNQ U 1 Astyanax mexicanus (Mexican tetra)
Q68ED3 Papd5
PAPD5_MOUSE
18 25 LAVPAEQRDFLPLETTNNNN U 1 Mus musculus (House mouse)
1 
Q8NDF8 PAPD5
PAPD5_HUMAN
18 25 HALPAEQRDFLPLETTNNNN U 2 Homo sapiens (Human)
1 
Please cite: ELM 2016-data update and new functionality of the eukaryotic linear motif resource. (PMID:26615199)

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