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Published in final edited form as: Curr Opin Struct Biol. 2020 Nov 2;67:86–94. doi: 10.1016/j.sbi.2020.09.010

RNA helicases are hubs that orchestrate exosome-dependent 3′–5′ decay

Eva-Maria Weick a, Christopher D Lima a,b
PMCID: PMC8087718  NIHMSID: NIHMS1633090  PMID: 33147539

Abstract

The RNA exosome is a conserved complex of proteins that mediates 3′ – 5′ RNA processing and decay. Its functions range from processing of non-coding RNAs such as ribosomal RNAs and decay of aberrant transcripts in the nucleus to cytoplasmic mRNA turnover and quality control. Ski2-like RNA helicases translocate substrates to exosome-associated ribonucleases and interact with the RNA exosome either directly or as part of multi-subunit helicase-containing complexes that identify and target RNA substrates for decay. Recent structures of these helicases with their RNA-binding partners or the RNA exosome have advanced our understanding of a system of modular and mutually exclusive contacts between the exosome and exosome-associated helicase complexes that shape the transcriptome by orchestrating exosome-dependent 3′ – 5′ decay.

Keywords: RNA exosome, Ski2-like helicases, 3′ – 5′ RNA decay, RNA-binding proteins

Introduction

The eukaryotic RNA exosome is a conserved protein complex and nexus for 3′ – 5′ RNA processing and decay. Its non-catalytic core includes a pseudo-hexameric RNAse PH-like ring that is capped by three S1/KH-related proteins that form a barrel-shaped structure with a central channel large enough to accommodate single-stranded RNA. Activities that degrade RNA reside in two associated 3′ end- and magnesium-dependent hydrolytic exoribonucleases, the RNAse D-like exoribonuclease Rrp6/EXOSC10 that interacts at the “top” of the S1/KH-cap and the RNAse II-like exoribonuclease Rrp44/DIS3 that interacts at the “bottom” of the core [1, 2]. Rrp6/EXOSC10 degrades RNA from the 3′ end with a distributive mechanism that liberates single nucleotide products along with release of substrate after one or more cleavage events. Rrp44/Dis3 also degrades RNA from the 3′ end and releases one nucleotide at a time, but functions as a processive enzyme that holds onto substrate after each cleavage so as to completely degrade one substrate before binding another. In addition, Rrp44/Dis3 harbors metal-dependent endoribonuclease activity that makes an internal cleavage and does not require a 3′ or 5′ RNA end.

The RNA exosome catalyzes maturation and/or decay of diverse substrates including pre-rRNAs, telomerase RNA, unstable transcripts such as enhancer RNAs (eRNAs), cytoplasmic mRNAs, and viral RNAs [3]. Substrate selectivity is not inherent to the exosome but is established by multi-subunit helicase complexes that target RNA. In the cytoplasm, Ski7/HBS1L3 connects the exosome to the Ski complex that functions in co-translational mRNA quality control. The Ski complex includes the Ski2 helicase, the tetratricopeptide repeat-containing protein Ski3 and two copies of the WD40-repeat protein Ski8 [4–6]. In the nucleus, the Ski2-like helicase Mtr4 interacts with the exosome via two adapters, M-phase phosphoprotein 6 (MPP6) and the Rrp6/EXOSC10-interaction partner Rrp47/C1D/Lrp1 [7]. Mtr4 is also a subunit of the Trf4/Trf5-Air1/Air2 polyadenylation (TRAMP) complex, which contains one of two non-templated RNA-polymerases, Trf4 or Trf5, and one of two zinc finger proteins, Air1 or Air2 (ZCCHC7 in human). In S. cerevisiae, TRAMP substrates include rRNA, snRNA, snoRNA precursors and some Pol II transcripts [8]. In metazoans, TRAMP appears restricted to the nucleolus, but MTR4 forms at least two nucleoplasmic complexes: The NEXT complex degrades short transcripts lacking mature polyA tails (e. g. eRNAs) and contains MTR4, the RNA-binding protein RBM7, and the zinc finger protein ZCCHC8 while the PAXT connection targets longer, polyadenylated transcripts and contains MTR4 and the zinc finger protein ZFC3H1 that interacts with RNA-binding proteins such as nuclear polyA binding protein PABPN1 [9–11]. NEXT and PAXT are targeted to transcripts via interactions with cap-binding proteins CBP80, CBP20, ARS2 and ZC3H18. Although substrate specificity for NEXT and PAXT overlap, MTR4 interactions with components of NEXT or PAXT appear mutually exclusive inside cells [9,11].

Here, we describe mechanisms underlying recruitment of Ski2-like helicases to the exosome and how mutually exclusive interactions with these helicases – particularly Mtr4 – create a modular and likely hierarchical platform that targets substrates for degradation. Finally, we highlight structural bases for disease-causing mutations in the 3′ – 5′ decay apparatus.

RNA exosome architectures

Early studies resolved a structure for the human nine-subunit exosome core (Exo9) (Fig 1a) [12]. Structures of ten- and eleven-subunit complexes from S. cerevisiae with Rrp6 and Rrp44 bound to RNA provided evidence that ribonucleases associate with the top and bottom of the core, respectively, and that RNA is engaged by the Exo9 central channel (Fig 1b, c) [13–15] while structures of a cytoplasmic complex with Exo9, Dis3 and Ski7 highlighted that Ski7 and Rrp6 utilize mutually exclusive surfaces for interaction with Exo9 (Fig 1c, d) [6,16].

Figure 1. Structures of RNA exosomes in complex with ribonucleases, an RNA helicase and adapter proteins.

Figure 1

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a) Structural overview and cartoons of the nine-component core of the human RNA exosome. Far left, left and center panels showing “top”, “bottom” and side view of the RNA exosome core. Individual subunits colored and labeled: EXOSC1/Csl4 = light blue, EXOSC2/Rrp4 = pale green, EXOSC3/Rrp40 = magenta, EXOSC4/Rrp41 = purple, EXOSC5/Rrp46 = green, EXOSC6/Mtr3 = orange, EXOSC7/Rrp42 = red, EXOSC8/Rrp43 = yellow, EXOSC9/Rrp45 = blue. Right panel illustrates a simplified schematic for the six-component pseudo-hexameric ring (gray) and three-component S1/KH cap (wheat), a format used in subsequent renderings. Far right panel depicts the central channel after slabbing into the exosome core. PDB: 6D6R

b) Cartoon representations of proteins and complexes shown in c) – g). The core (gray and wheat), with ribonuclease Rrp44/DIS3 in light pink and Rrp6/EXOSC10 in medium blue. Exosome adapters that recruit other proteins to the complex are shown in dark blue (Ski7), olive (Rrp47/C1D), and dark red (MPP6). The MTR4 helicase is shown in teal and nucleic acid is depicted in orange throughout.

c) Surface rendering of a nuclear 11-component RNA-bound S. cerevisiae exosome with Rrp6 (medium blue) occupying the top of the exosome core and Rrp44 (light pink) at the bottom of the core. PDB: 5K36

d) Structure of a cytoplasmic 11-component RNA-bound S. cerevisiae exosome associated with the Ski-complex adapter Ski7 (dark blue) and Rrp44 (light pink). PDB: 5JEA

e) Structure of a nuclear RNA-bound 12-component S. cerevisiae exosome with its associated ribonucleases as well as the nuclear Rrp6-interacting protein Rrp47 (olive). PDB: 5C0W

f) Structure of a S. cerevisiae nuclear RNA-bound 12-component exosome with its associated ribonucleases and helicase-recruiting protein Mpp6 (dark red). PDB: 5VZJ

g) Structure of a human nuclear 14-component RNA exosome with the helicase MTR4 (teal), MPP6 (dark red), ribonucleases DIS3 (light pink) and EXOSC10/Rrp6 with C1D/Rrp47, and RNA. The majority of EXOSC10/Rrp6 and C1D/Rrp47 (both shown in transparent cartoon representation to the side) were presumed disordered in this cryo-EM structure because a segment of EXOSC10/Rrp6 (medium blue; indicated by magenta arrow) was observed bound to the core. PDB: 6D6R

Locations for helicase-interacting adapter proteins were revealed by 12-subunit nuclear exosome structures, one with Dis3, Rrp47 and Rrp6 (Fig 1e), the other with Dis3, Rrp6 and Mpp6 (Fig 1f) [17,18]. The N-terminal regions of Rrp47 and Rrp6 form a helical bundle with the N-terminal region of Mtr4 [19] while Mpp6 contacts Mtr4 and the core via its N-terminal and central region, respectively [18]. These structures suggested that the helicase is recruited to the top of the exosome. Indeed, structures of 14-subunit human nuclear exosome complexes with MTR4 show that MTR4 binds to MPP6 and EXOSC2/Rrp4 on top of the exosome core (Fig 1g) [20,21]. Notably, these structures also suggest mutual exclusivity with respect to interactions of MTR4 and EXOSC10/Rrp6 with EXOSC2/Rrp4. While EXOSC10/Rrp6 remains tethered to the PH-like ring, RNA-bound MTR4 displaces the EXOSC10/Rrp6 catalytic domain from the top of the core.

Helicases as recruitment platforms for RNA-binding complexes

Ski2-like helicases belong to the SF2 superfamily and contain two RecA domains, RecA1 and RecA2, a winged helix (WH) domain and a helical bundle (HB) that encircle single-stranded nucleic acid [22]. Mtr4 and Ski2 contain an insertion in the WH domain called the Arch (Fig 2a, b) [22], that includes two antiparallel coiled coils that form an arm or “stalk” and a globular “fist”. In Mtr4 the fist contains a Kyrpides-Ouzounis-Woese (KOW) motif typically found in RNA-binding ribosomal proteins [23,24]. RNA contacts with the RecA, HB and Arch domains are shown in Fig 2c.

Figure 2. The Ski2-like helicase Mtr4 establishes contacts through modular interaction surfaces.

Figure 2

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a) Schematic of MTR4, a Ski2-like helicase. The N-terminal domain (N-ter; gray) includes regions that are predicted to be largely unstructured. RecA1 (pale green) and RecA2 (pink) domains are followed by a winged helix (WH) domain (teal) that contains the characteristic Arch insertion domain (turquoise). The C-terminal HB (helical bundle) domain is in blue.

b) Side view of a crystal structure of the human MTR4 helicase and its domains in a closed Arch conformation. Colors as in schematic in a), ATP (shown as spheres) is visible in the background. RNA path is traced as dark gray dotted line. Orientation on the left is the same side view displayed in panels c) (left) and e) to j). PDB: 6IEH.

c) The S. cerevisiae Mtr4 helicase bound to RNA as viewed from the side (left) and top (right). The 7S rRNA substrate is orange and the 25S rRNA is bright green. PDB: 6FT6, 6FSZ

d) Magnified view of interactions between the conserved arginine residues Arg658 and Arg743 (Arg678 and Arg774 in S. cerevisiae) of MTR4 (light blue) and the arch-interacting motif (AIM) of yeast Nop53 (top panel, salmon) compared to human NVL (bottom panel, orange). The original “canonical” AIM LFXΦD where X represents any amino acid and Φ represents any hydrophobic amino acid is exemplified by Nop53. The AIM of NVL is shown to illustrate how divergent sequences interact within the same surface on MTR4. * indicates residues that were modelled as alanine in the structure. PDB ID: 5OOQ, 6ROI

e) Structure of budding yeast Mtr4 (light blue) with the Mtr4-interacting domain of Nop53 (salmon) bound to the Arch domain. Compare to Figure 2d, top panel for magnified view of this interaction. PDB: 5OOQ

f) Structure of human MTR4 with an N-terminal fragment of the human ribosome assembly factor NVL (orange). Compare to Figure 2d, bottom panel for magnified view of this interaction. PDB: 6RO1

g) Structure of human MTR4 (Δ N-ter) in light blue in complex with an N-terminal fragment of the nuclear protein NRDE2 (beige) that binds the Arch before forming contacts with the HB and RecA2 domains. PDB: 6IEH

h) Structure of human MTR4 with the N-terminal region of MPP6 (dark red) nestled between RecA1 and RecA2. The Arch insertion domain is present and observed in two conformations in a subset of particles but is mobile in the composite of this cryo-EM structure so is schematically outlined as dashed lines here. PDB: 6D6R, EMDB: EMD-7818 and EMD-7819.

i) Structure of human MTR4 in complex with a C-terminal fragment of ZCCHC8 (lime). The N-terminal region and Arch domain were deleted from this construct of MTR4. ZCCHC8 inserts between the RecA1 and WH domain (not visible in view displayed) then runs along the base of the helicase core and inserts its C-terminal region between the RecA1 and RecA2 domains of MTR4. PDB: 6C90

j) Structure of budding yeast Mtr4 bound to an Air2-Trf4 peptide fusion construct with the Air2 N-terminal region in teal and Trf4 in pink. PDB: 4U4C

Proteins contact the Mtr4 KOW domain in a mutually exclusive manner through van der Waals contacts and electrostatic interactions with conserved arginine residues in Mtr4 (Arg658 and Arg743 in human, Arg678 and Arg774 in S. cerevisiae). In yeast, an Arch-Interacting Motif (AIM) LFXΦD was identified in ribosome maturation factors, Utp18 and Nop53 (Fig 2d top panel), that function in early 5′ ETS (external transcribed spacer) and late 7S rRNA processing, respectively [24]. Data from a human biogenesis factor NVL (Rix7 in yeast) (Fig 2d bottom panel) and NEXT ZCCHC8 suggest that AIMs can be degenerate, thus precluding straightforward identification of MTR4-interacting proteins [25]. While motifs vary, structures of yeast Nop53 and human NVL AIMs reveal that AIM-binding sites on Mtr4 appear conserved (Fig 2d, e, f) [25,26]. An N-terminal portion of NRDE-2 also engages the Arch with contacts extending further to the HB and RecA2 domain (Fig 2g) resulting in a “closed” conformation of MTR4 that likely prevents its interaction with the exosome [27].

Competition for binding Mtr4 is not limited to the Arch. MPP6 bridges EXOSC1/Csl4 and EXOSC3/Rrp40 with its central domain while contacting MTR4 RecA1 and RecA2 domains with its N-terminal region (Fig 1g, Fig 2h). The C-terminal region of NEXT ZCCHC8 engages a similar surface on MTR4, albeit in an opposing orientation (Fig 2i) [20,28]. These data suggest that interactions between MTR4, MPP6 and ZCCHC8 are mutually exclusive.

Finally, a structure of S. cerevisiae Mtr4 shows that the N-terminal region of TRAMP Air2 wraps around the HB and RecA2 domains while part of Trf4 engages the RecA2 domain (Fig 2j) [29]. Air2 also contains a canonical AIM that is thought to interact with Mtr4.

The Arch domain of Mtr4 and Ski2 can also interact with RNA (Fig 2c). Unlike the mutual exclusivity observed between proteins engaging MTR4, competition between RNA and protein cofactors binding to helicase surfaces has yet to be documented [20,29,30].

Interactions with the ribosome

Complexes between the 3′ – 5′ decay apparatus and the ribosome illustrate how helicases orchestrate recruitment of RNA to the exosome for maturation or degradation. A structure of a S. cerevisiae pre-60S ribosome RNA processing complex (Fig 3a) shows Mtr4 interactions with 25S rRNA via its Arch, RecA2 and HB domains, Rrp47 contacts with ribosomal biogenesis protein Nop7, and a path for 5.8S+30nt rRNA from the pre-60S ribosome through Mtr4 and the exosome central channel to Dis3 [30]. As processing and decay are considered discrete functions, it is notable that this complex shares many similarities with a human RNA decay complex (compare Fig 1g and Fig 3a) [20].

Figure 3. Complexes between the ribosome and Ski2-like helicase assemblies.

Figure 3

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a) Structure of an rRNA processing complex between the S. cerevisiae pre-60S ribosome and Mtr4 helicase-exosome. Left: overview of the complete ribosome-exosome structure. Surfaces for pre-60S proteins and rRNAs (except 7S rRNA) in pale green, the exosome core in gray and wheat for the PH-ring and the S1/KH cap, respectively. Dis3 in light pink and the body of Rrp6 in blue. The 7S rRNA substrate is highlighted in orange. Mtr4 is in teal with its exosome interaction partners Rrp47 and the Rrp6 N-terminal region in olive and blue, respectively. Right top inset: Mtr4 domain structure is visualized as in Fig 2a with the N-terminal domain (N-ter) in gray, RecA1 in pale green, RecA2 in pink, the winged helix (WH) domain in teal the Arch insertion domain in turquoise and the helical bundle (HB) in blue. The view presented here is the same as in the overview and the inset on the bottom. Right bottom inset: magnified view of the Mtr4 helicase (teal) making contacts with the 25S rRNA (green) via its Arch and RecA2 domains. Additional interactions occur between the ribosomal protein Nop7 (yellow) and the C-terminal region of exosome adapter Rrp47 (olive). Mpp6 (dark red) is visible in the background. PDBs: 6FT6, 6FSZ

b) Structure of an mRNA degrading complex between budding yeast Ski and the ribosome. Left: overview of the ribosome-Ski complex. Surfaces for 60S and 40S ribosome subunits in pale green and pale blue, respectively. The mRNA substrate is orange. The Ski2 helicase is dark green, with Ski3 shown in raspberry and the two Ski8 subunits shown in wheat and gold. Top right inset: Ski2 domain structure is visualized as in Fig 2a with the RecA1 domain in pale green, RecA2 in pink, the winged helix domain in teal the Arch insertion domain in turquoise and the helical bundle in blue. The view presented is the same as in the overview and bottom right panel except that the N-terminal domain of Ski2 which is visible in the overview is omitted. Bottom right inset: magnified, slabbed view of Ski2 (dark green) contacting the 18S rRNA (dark red) via its Arch and RecA2 domains. Interactions also occur between the Arch of Ski2 and ribosomal protein uS10 (salmon) and between the helicase core and uS3 (purple) and eS10 (blue) of the 40S ribosomal subunit. Contacts between one of the Ski8 monomers and the ribosome are not shown. PDB: 5JEA

A structure of a cytoplasmic S. cerevisiae 80S ribosome with the Ski complex shows a non-STOP mRNA substrate engaged by the Ski2 helicase as it emerges from the exit channel of the 40S subunit. Ski2 interacts with 40S rRNA and proteins via its RecA2 and Arch domains (Fig 3b) [31]. It remains unclear if Ski recruits the exosome to the ribosome, or if the Ski-RNA complex dissociates before engaging the exosome.

The RNA exosome and its interaction partners in disease

Biallelic variants in core subunits are correlated with developmental delays and neurodegenerative disease (supplemental table 1; reviewed in [32]). Exosomopathies are rare and clinically variable, sometimes even between alleles in the same subunit. Thus, it remains challenging to distinguish between missense alleles that abrogate protein expression from those that partially disrupt function through perturbation of a particular activity or binding surface. The consequence of missense alleles on structure is hypothesized for disease alleles where sufficient structural or experimental data is available (Fig 4a).

Figure 4. RNA exosome-associated proteins in human disease.

Figure 4

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a) Structure of the RNA-bound 14-component human exosome complex with the location of disease-associated residues shown as purple spheres with close-ups for respective positions shown in panels b) to d). Nucleic acid is colored orange and represented by a dashed line in areas where density is discontinuous. PDB: 6D6R

b) Selected mutations in EXOSC3/Rrp40 that are associated with pontocerebellar hypoplasia type 1B: Gly191Cys and Trp238Arg (protein in pink, disease residues in purple). Trp238 is part of a hydrophobic patch adjacent to the interaction surface with Exosc9/Rrp45 (blue). MPP6 is shown in dark red. Figure illustrates wild-type amino acids corresponding to disease alleles. PDB: 6D6R

c) Leu206 (purple) in EXOSC5/Rrp46 (green) is shown at the hydrophobic interface between EXOSC5/Rrp46 and EXOSC9/Rrp45 (yellow). Figure illustrates wild-type amino acids corresponding to disease alleles. PDB: 6D6R

d) The exoribonuclease active site for DIS3/Rrp44 (light pink) illustrating four residues linked to multiple myeloma in multiple patients (Asp487His/Val, Asp488Asn/Gly/His, Arg780Lys, Cys483Trp; all highlighted in purple) and RNA substrate (orange). Mg2+ ions could not be unambiguously assigned in the human cryo-EM structure and some side chain conformations (Asp479) differ when comparing the human structure to yeast Dis3 and bacterial ribonuclease II. Figure illustrates wild-type amino acids corresponding to disease alleles. PDB: 6D6R

e) The S. cerevisiae Ski complex includes Ski2 (green), Ski3 (raspberry), and two copies of Ski8 (wheat and gold). Mutations are highlighted with purple spheres on the yeast Ski2 structure at positions homologous to those in patients with Syndromic Diarrhea/Tricho-Hepato-Enteric Syndrome. PDB: 4BUJ

f) Budding yeast Glu459 and Trp487 (purple) are homologous to human patient alleles Glu438Lys and Trp466Gly and are shown within the RecA2 domain of Ski2 (green). Figure illustrates wild-type amino acids corresponding to disease alleles. PDB: 4BUJ

Mutations in EXOSC3/Rrp40 (Gly191Cys, Trp238Arg) are associated with pontocerebellar hypoplasia type 1B and occur at the interface between EXOSC3/Rrp40, MPP6 and EXOSC9/Rrp45 (Fig 4b). A polar interaction between Arg74 of MPP6 and the backbone carbonyl group of Gly189 is likely disrupted by Gly191Cys mutation [20]. The importance of MPP6 Arg74 is suggested because mutation of the analogous yeast residue results in reduced decay activity in vitro [18]. Trp238Arg is predicted to disrupt interactions with MPP6 by removing a hydrophobic patch in EXOSC3/Rrp40 adjacent to the interface between EXOSC3/Rrp40, MPP6, and EXOSC9/Rrp45. The added positive charge could also repel MPP6 Arg74.

Slavotinek et al. [33] show how missense mutations in exosome proteins may disrupt subunit interactions even when proteins are expressed at normal levels. EXOSC5/Rrp46 Leu206, for example, is highly conserved, embedded within the interface between EXOSC5/Rrp46 and EXOSC8/Rrp43, and Leu206His substitution interferes with binding of EXOSC5 to other exosome subunits (Fig 4c) [33].

Mutations in the DIS3 ribonuclease occur in multiple myeloma [34]. The most frequent mutations (Asp487His/Val, Asp488Asn/Gly/His, Arg780Lys and Cys483Trp) occur within the exoribonuclease active site and likely result in catalytically inactive protein that can bind but not hydrolyze RNA. Based on conservation with yeast Rrp44 and E. coli RNase II, human DIS3 Asp479, Asp488, Asp485 and Asp487 coordinate two Mg2+ ions that activate water for hydrolytic cleavage (Fig 4d) [35]. Arg780 is conserved and contacts the last two RNA bases as well as the scissile and penultimate phosphates, interactions that could be disrupted by mutation to lysine [35].

Mutations are also observed in NEXT and Ski components. For NEXT, fusions of ZCCHC8 to the Ros kinase occur in different malignancies [36–38] and a heterozygous loss of function (LOF) allele (Pro186Leu) results in a short telomere syndrome with familial pulmonary fibrosis, likely due to lower expression of ZCCHC8 [39]. A mutation (Pro79Arg) in NEXT RBM7 is correlated with a spinal muscular atrophy-like disease and patient cells have reduced levels of RBM7 [40]. For Ski, mutations in SKIV2/Ski2 and TTC37/Ski3 are associated with syndromic diarrhea and Tricho-Hepato-Enteric syndrome SD/THES (Fig 4e) [41–46]. Most alleles are deletions or premature stop codons and homozygous missense mutations such as SKIV2 Glu438Lys (Glu459 in yeast) or Trp466Lys (Trp487 in yeast) are presumably tantamount to LOF alleles (Fig 4f) likely destabilizing the helicase core [4]. Interestingly, Ski and TRAMP are also linked to antiviral immunity and immunodeficiency is common in SD/THES patients [45,47].

Conclusions

Here we describe recent structural underpinnings related to Ski2-like helicases and their roles in recruiting RNA and RNA-binding proteins to the exosome. In particular nuclear Mtr4 engages in several presumably mutually exclusive interactions with cofactors and the exosome. Mechanisms underlying the hierarchy of these interactions remain understudied: are interactions dependent on binding affinity, localization, RNA association, or do post-translational modifications play a role? Further understanding of helicase-exosome decay axes will depend on uncovering a structural basis for NEXT, TRAMP and PAXT including their activities and ability to associate with the transcription apparatus and the exosome. Advanced in situ imaging such as cryo-electron tomography coupled with fluorescence microscopy (see [48]) may provide further clues by visualizing these complexes in their cellular milieu, especially in the context of ongoing transcription, ribosome maturation, and co-translational quality control. Ultimately, such insights may further our understanding of the biology of RNA exosome-linked disease.

Supplementary Material

1

Highlights.

  • RNA exosome structures with nuclear and cytoplasmic interaction partners

  • Ski2-like helicases are organizing hubs for substrate recruitment complexes

  • Hierarchical RNA binding and decay suggested by mutually exclusive interactions

  • Structural basis for missense disease alleles in 3′ – 5′ RNA decay

Acknowledgements

We thank members of the Lima laboratory for helpful discussions. This research was supported in part by the National Institute of General Medical Sciences of the National Institutes of Health R35GM118080 (C.D.L.). The content is the authors’ responsibility and does not represent the official views of the NIH. C.D.L is a Howard Hughes Medical Institute Investigator.

Footnotes

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The authors declare no conflict of interest.

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