ELM - Detail for LIG_MTR4_AIM

Accession:	ELME000551
Functional site class:	MTR4 arch domain ligand
Functional site description:	The MTR4 helicase is an essential component of nuclear exosomes that contributes to the processing or degradation of different types of RNA. Besides its helicase activity, MTR4 also serves as an interaction platform for diverse nuclear exosome adaptor proteins that utilize their MTR4 arch domain-interacting motif (AIM) to recruit the exosome to different RNA substrates, thereby facilitating their efficient processing or degradation.
ELM Description:	The AIM motif has been described in several nuclear exosome adaptor proteins that form a complex with yeast (4U4C; 5OOQ) or human MTR4 (6RO1; 6IEH). The motifs adopt very similar conformations in the different complexes (Dobrev,2021), regardless of the observations that some adaptors, such as Air2, ZCCHC8 and NRDE2 establish an extensive interaction interface with MTR4, wherein the AIM motif is only a subregion (Falk,2014; Lingaraju,2019; Wang,2019). The AIM motif adopts an extended conformation on the top of the MTR4 KOW subdomain of arch. The first 3 AIM residues (P1 - aromatic, P2 – anything but Proline and P3 - a hydrophobic residue) bind by β-augmentation, forming a short antiparallel β-strand with the β5 strand of the KOW β-barrel. P2 makes two H bonds to KOW β5. A 3rd H bond is made by the backbone amide of P4. The side chains of the aromatic and hydrophobic residues of the short β strand are in vdW contacts with an apolar patch of the KOW domain. The conserved Asp residue at P4 ends the short β-strand, forming two salt-bridges, one with the exposed Arg774 (equivalent to Arg 743 in human MTR4) and one with the buried Arg678 that is part of the KOW core (Falk,2017). Mutations to these charged residues that are conserved from yeast to human eliminate motif binding (Falk,2017; Thoms,2015). Following these core residues of the AIM motif, the backbone needs to bend. This is usually solved by a small (G/A/P/S) residue 3 positions downstream of the conserved aspartic acid. These residue-residue interactions are generally preserved in the AIM complexes. Additionally, further interactions have been identified in individual complexes. For instance, in the complex of yeast Nop53 a conserved Leu residue preceding the first aromatic position of the motif was observed to make contacts with Mtr4, as well as a Val residue directly following the conserved aspartic acid. However, these residues are not conserved in all the hitherto described AIM instances.
Pattern:	`[FYW][^P][VILTM]D.(([^P][GPAS])\|G)`
Pattern Probability:	`0.0001554`
Present in taxon:	Eukaryota
Interaction Domain:	rRNA-processing arch domain (IPR025696) The essential RNA helicase Mtr4 is an exosome-activating cofactor (Stochiometry: 1 : 1)

MTR4 arch domain ligand

The MTR4 helicase is an essential component of nuclear exosomes that contributes to the processing or degradation of different types of RNA. Besides its helicase activity, MTR4 also serves as an interaction platform for diverse nuclear exosome adaptor proteins that utilize their MTR4 arch domain-interacting motif (AIM) to recruit the exosome to different RNA substrates, thereby facilitating their efficient processing or degradation.

ELM Description:

The AIM motif has been described in several nuclear exosome adaptor proteins that form a complex with yeast (4U4C; 5OOQ) or human MTR4 (6RO1; 6IEH). The motifs adopt very similar conformations in the different complexes (Dobrev,2021), regardless of the observations that some adaptors, such as Air2, ZCCHC8 and NRDE2 establish an extensive interaction interface with MTR4, wherein the AIM motif is only a subregion (Falk,2014; Lingaraju,2019; Wang,2019).
The AIM motif adopts an extended conformation on the top of the MTR4 KOW subdomain of arch. The first 3 AIM residues (P1 - aromatic, P2 – anything but Proline and P3 - a hydrophobic residue) bind by β-augmentation, forming a short antiparallel β-strand with the β5 strand of the KOW β-barrel. P2 makes two H bonds to KOW β5. A 3rd H bond is made by the backbone amide of P4. The side chains of the aromatic and hydrophobic residues of the short β strand are in vdW contacts with an apolar patch of the KOW domain. The conserved Asp residue at P4 ends the short β-strand, forming two salt-bridges, one with the exposed Arg774 (equivalent to Arg 743 in human MTR4) and one with the buried Arg678 that is part of the KOW core (Falk,2017). Mutations to these charged residues that are conserved from yeast to human eliminate motif binding (Falk,2017; Thoms,2015). Following these core residues of the AIM motif, the backbone needs to bend. This is usually solved by a small (G/A/P/S) residue 3 positions downstream of the conserved aspartic acid. These residue-residue interactions are generally preserved in the AIM complexes.
Additionally, further interactions have been identified in individual complexes. For instance, in the complex of yeast Nop53 a conserved Leu residue preceding the first aromatic position of the motif was observed to make contacts with Mtr4, as well as a Val residue directly following the conserved aspartic acid. However, these residues are not conserved in all the hitherto described AIM instances.

Pattern:

[FYW][^P][VILTM]D.(([^P][GPAS])|G)

Pattern Probability:

0.0001554

Present in taxon:

Eukaryota

Interaction Domain:

rRNA-processing arch domain (IPR025696) The essential RNA helicase Mtr4 is an exosome-activating cofactor (Stochiometry: 1 : 1)

MTR4 (P42285) is a multidomain RNA helicase, an essential co-factor of the nuclear exosome that mediates the nuclear processing or degradation of diverse RNA species. Besides its RNA unwinding helicase activity, MTR4 is also bound by diverse RNA-binding proteins that function as adaptors (so called nuclear exosome adaptors) in different RNA processing and decay pathways by recruiting the exosome to different types of substrate RNAs. These adaptors often employ so-called arch domain-interacting motifs (AIM) to bind to the KOW domain (part of arch) of MTR4 in a mutually exclusive manner (Thoms,2015; Lingaraju,2019; Falk,2017).

In yeasts, the AIM-mediated interaction of Mtr4 (P47047) and Nop53 (Q12080) recruits the nuclear exosome to the pre-60S RNP, thereby facilitating the maturation of the 5.8S rRNA, while the Mtr4-Utp18 interaction (Utp18 is another ribosome biogenesis factor, P40362)) directs the exosome to an earlier preribosomal particle (Thoms,2015; Falk,2017). Mtr4 is also part of the TRAMP complex that is involved in the nuclear turnover of noncoding RNAs and intergenic transcripts. Therein Trf4 and Air2 (that constitute the poly(A)polymerase subunit of the complex) establish an intricate relationship with Mtr4, including an AIM-mediated interaction by Air2 (Falk,2014).

In humans, the homolog of yeast Nop53 was similarly shown to contact MTR4 through an AIM, as well as the early ribosome biogenesis factor NVL (O15381) as does the ZCCHC8 (Q6NZY4) subunit of the Nuclear Exosome Targeting (NEXT) Complex. This complex mediates the targeting of enhancer RNAs (eRNAs), promoter upstream transcripts (PROMPTs) and intronic RNAs for exosome-mediated decay (Lingaraju,2019).

While, nuclear exosome adaptors generally promote exosome activity, NRDE2 (Q9H7Z3) relocalizes MTR4 into nuclear speckles by establishing a special, intricate relationship with the helicase, wherein it completely wraps around MTR4 and blocks the binding sites of both exosome adaptor proteins that could recruit MTR4 to different RNA species, and the exosome itself (6IEH). It keeps MTR4 in a closed conformation wherein although it retains helicase activity and is capable of RNA binding, is still inactive due to the loss of interactions with exosome and adaptor proteins (Wang,2019). Within the larger meandering NRDE2:MTR4 interaction surface, the AIM-like region is just a small, but essential subregion, one of the many contact points NRDE2 establishes with MTR4 to outcompete other protein partners (Wang,2019).

Some other AIM-containing adaptors also contact MTR4 through several interaction interfaces, for instance, ZCCHC8 also contacts and regulates the activity of the MTR4 helicase core and binds another patch on the arch domain through a non-canonical, so-called I-AIM (Lingaraju,2019). Yeast Air2 also establishes a large interaction surface with Mtr4, wherein, besides the arch domain, it also contacts the RecA2 and helical bundle domains (Falk,2014).

Biological Process:
Mrna Processing (also annotated in these classes: )
Nuclear Rna Surveillance (also annotated in these classes: )
Regulation Of Mrna Catabolic Process (also annotated in these classes: )
Rrna Processing (also annotated in these classes: LIG_Trf4_IWRxY_1 )
Snrna Catabolic Process (also annotated in these classes: LIG_Trf4_IWRxY_1 )
Rna Catabolic Process (also annotated in these classes: LIG_Trf4_IWRxY_1 )
Cellular Compartment:
Protein-Containing Complex (also annotated in these classes: )
Tramp Complex (also annotated in these classes: )
Nucleus (also annotated in these classes: )
Molecular Function:
Protein Domain Specific Binding (also annotated in these classes: )
Protein Binding (also annotated in these classes: )

Acc., Gene-, Name	Start	End	Subsequence	Logic	#Ev.	Organism	Notes
Q12476 AIR2 AIR2_YEAST	8	14	EKNTAPFVVDTAPTTPPDKL	TP	7	Saccharomyces cerevisiae S288c	4U4C 4U4C 1
Q9H7Z3 NRDE2 NRDE2_HUMAN	163	169	AVTGETFRTDKKPDPANWEY	TP	9	Homo sapiens (Human)	6IEH 6IEH 1
Q6NZY4 ZCCHC8 ZCHC8_HUMAN	178	184	VLYFTNFCLDKLGQPLLNEN	TP	4	Homo sapiens (Human)	1
Q9NZM5 NOP53 NOP53_HUMAN	87	93	APNEKLFFVDTGSKEKGLTK	TP	3	Homo sapiens (Human)	1
O15381 NVL NVL_HUMAN	173	179	KDSEGGWFIDKTPSVKKDSF	TP	9	Homo sapiens (Human)	6RO1 6RO1 1
P40362 UTP18 UTP18_YEAST	85	91	VNNDQLFFVDDGGNEDSQDK	TP	7	Saccharomyces cerevisiae S288c	1
Q12080 NOP53 NOP53_YEAST	61	67	LQNDALFHVDVEGDEILKNK	TP	11	Saccharomyces cerevisiae S288c	5OOQ 5OOQ 1
P53866 SQS1 SQS1_YEAST	208	214	VEDGDLFFVDEEAQQSPDLT	TP	4	Saccharomyces cerevisiae S288c	1

Acc., Gene-, Name

Start

End

Subsequence

Logic

#Ev.

Organism

Notes

Q12476 AIR2
AIR2_YEAST

EKNTAPFVVDTAPTTPPDKL

Saccharomyces cerevisiae S288c

4U4C