Affinage

SKIC2

Superkiller complex protein 2 · UniProt Q15477

Length
1246 aa
Mass
137.8 kDa
Annotated
2026-06-10
25 papers in source corpus 8 papers cited in narrative 8 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/7 claims corpus-supported (86%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

SKIC2 (SKI2/SKI2W/SKIV2L) is a DExH-box RNA helicase that drives cytoplasmic 3'-to-5' mRNA decay as the catalytic engine of the Ski2-Ski3-Ski8 (SKI) complex, acting together with the RNA exosome in both general mRNA turnover and quality control (PMID:9482746). The protein carries a DEVH-box helicase signature and possesses intrinsic ATPase activity (PMID:7610041). Within the complex, Ski3 functions as a scaffold whose C-terminus binds Ski8 and whose sub-C-terminal region binds Ski2, with no direct Ski2-Ski8 contact; the helicase activity of Ski2 is dispensable for complex assembly, since helicase-dead mutants still associate with Ski7 (PMID:16043509). Structurally, the Ski2 helicase region adopts an Mtr4-like architecture with an extended insertion domain that serves as a broad-specificity RNA-binding module rather than a complex-assembly element (PMID:22114319). Mechanistically, the SKI complex docks directly onto 80S ribosomes presenting a short 3' mRNA overhang; ribosome binding displaces the autoinhibitory domain of Ski2 into an open conformation near the mRNA entry tunnel and threads the 3' overhang from the small subunit directly into the Ski2 helicase channel, priming it for exosome-mediated degradation (PMID:27980209). The human ortholog co-sediments with the 40S ribosomal subunit through salt- and RNase-resistant contacts and localizes to nucleoli and cytoplasm (PMID:9705521). Beyond core decay, human SKIC2 with the exosome degrades hepatitis B HBx mRNA, and its transcription is induced via IL-1β/ATF3 signaling acting on a CRE element in the SKIC2 promoter (PMID:30055801).

Mechanistic history

Synthesis pass · year-by-year structured walk · 8 steps
  1. 1995 Medium

    Establishing that SKI2 has a general cellular role beyond antiviral defense was the first step in recognizing it as a core mRNA decay factor rather than a virus-specific repressor.

    Evidence Genetic synthetic lethality of sep1/xrn1 ski2 double mutants in virus-cured yeast strains with cell cycle arrest at Start

    PMID:7739552

    Open questions at the time
    • The molecular basis of the general function was inferred genetically, not demonstrated biochemically
    • Did not directly link SKI2 to the 3'-5' decay machinery
  2. 1995 Medium

    Identifying the human SKI2W ortholog as a DEVH-box helicase with ATPase activity defined the enzyme's catalytic identity.

    Evidence Sequence analysis plus baculovirus expression and in vitro ATPase assay of the fusion protein

    PMID:7610041

    Open questions at the time
    • ATPase shown for a fusion protein in vitro; helicase (duplex unwinding) activity not directly demonstrated
    • No substrate specificity defined
  3. 1998 High

    Placing SKI2 within the 3'-5' decay pathway alongside exosome components defined its pathway membership and showed it is essential when combined with loss of 5'-3' decay.

    Evidence Genetic epistasis with ski3/ski6/ski8/rrp4 mutants, mRNA half-life measurements, and synthetic lethality with 5'-3' decay mutants in yeast

    PMID:9482746

    Open questions at the time
    • Did not resolve physical organization of the SKI complex
    • Direct biochemical coupling to the exosome not yet shown
  4. 1998 Medium

    Demonstrating physical association of human Ski2w with the 40S ribosomal subunit and its nucleolar/cytoplasmic localization connected the helicase to translating ribosomes.

    Evidence Sucrose gradient sedimentation, RNase A/high-salt-resistant co-sedimentation with 18S rRNA and S27a, and indirect immunofluorescence in HeLa cells

    PMID:9705521

    Open questions at the time
    • Functional consequence of 40S association not established
    • Nucleolar localization role uncharacterized
  5. 2005 High

    Defining the architecture of the SKI complex established Ski3 as the scaffold and showed helicase catalysis is separable from complex assembly.

    Evidence Directed yeast two-hybrid, reciprocal co-immunoprecipitation, and in vivo assays with helicase-dead Ski2p mutants

    PMID:16043509

    Open questions at the time
    • Stoichiometry and quantitative affinities not determined
    • Structural basis of the interactions not resolved
  6. 2011 High

    The crystal structure of the Ski2 helicase region defined its Mtr4-like fold and identified the insertion domain as a broad-specificity RNA-binding module.

    Evidence X-ray crystallography at 2.4 Å with in vitro RNA-binding and deletion-construct assays

    PMID:22114319

    Open questions at the time
    • Structure of full-length protein and assembled complex not captured
    • Mechanism of substrate channeling not shown
  7. 2016 High

    The cryo-EM ribosome-SKI structure resolved the central mechanistic question of how the complex extracts mRNA for decay, showing direct ribosome docking, autoinhibition relief, and 3'-overhang threading into the helicase channel.

    Evidence Cryo-EM of an endogenous 80S ribosome-Ski2-Ski3-Ski8 complex at ~4 Å core resolution

    PMID:27980209

    Open questions at the time
    • Direct handoff to the exosome not captured structurally
    • Dynamics of mRNA translocation through the channel not resolved
  8. 2018 Medium

    Linking human SKIC2/exosome activity to viral HBx mRNA decay and to IL-1β/ATF3 transcriptional induction connected the decay machinery to inducible antiviral gene regulation.

    Evidence Promoter-reporter assays, ChIP for ATF3 binding, siRNA knockdown, and mRNA stability assays

    PMID:30055801

    Open questions at the time
    • Single-lab study; direct helicase action on HBx mRNA not structurally resolved
    • Breadth of viral/cellular targets regulated this way unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the human SKI complex physically hands threaded mRNA to the exosome, and the functional role of SKIC2 nucleolar localization, remain unresolved.
  • No structure of the human SKI-exosome-ribosome supercomplex
  • Nucleolar function of human SKIC2 uncharacterized

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140098 catalytic activity, acting on RNA 2 GO:0003723 RNA binding 1 GO:0016787 hydrolase activity 1 GO:0140657 ATP-dependent activity 1
Localization
GO:0005840 ribosome 2 GO:0005730 nucleolus 1 GO:0005829 cytosol 1
Pathway
R-HSA-8953854 Metabolism of RNA 2
Partners
SKI7SKIC3SKIC8
Complex memberships
SKI complex (Ski2-Ski3-Ski8)

Evidence

Reading pass · 8 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1998 SKI2 is required for the 3' to 5' decay pathway of mRNA in yeast. Genetic experiments showed that ski2 mutants block 3' to 5' degradation of mRNA, and that SKI2 acts together with SKI3, SKI8, and exosome components (SKI6/RRP41, RRP4) to degrade mRNA bodies in a 3' to 5' direction. Blocking both 3' to 5' and 5' to 3' decay pathways simultaneously causes inviability with extremely long mRNA half-lives. Genetic epistasis with ski2/ski3/ski6/ski8/rrp4 mutants; mRNA half-life measurements; synthetic lethality with 5'-3' decay mutants The EMBO journal High 9482746
1995 sep1/xrn1 ski2 double mutants of S. cerevisiae are synthetically lethal independently of the killer virus (L-A and M dsRNA viruses), demonstrating that SKI2 performs a general cellular function beyond antiviral activity, proposed to involve blocking translation on transcripts targeted for degradation. The double mutants also show a synthetic cell cycle arrest in late G1 at Start. Genetic synthetic lethality screen; double-mutant analysis; virus-cured strains; temperature-sensitive alleles Molecular and cellular biology Medium 7739552
1995 The human SKI2W (SKIC2) protein contains consensus sequences for an RNA helicase with a DEVH box and has ATPase activity when expressed as a fusion protein in insect cells using a baculovirus vector. Sequence analysis; baculovirus expression; ATPase activity assay Nucleic acids research Medium 7610041
1998 Human Ski2w (SKIC2) protein is enriched in polysomal fractions of cytoplasmic extracts from HeLa cells and co-sediments with the 40S ribosomal subunit in the presence of EDTA. This association is resistant to RNase A treatment and 0.5 M KCl, indicating direct protein-protein contact with the 40S subunit. By indirect immunofluorescence, Ski2w is localized in nucleoli and cytoplasm. Sucrose gradient sedimentation; co-sedimentation with 18S rRNA and S27a protein; RNase A and high-salt resistance assay; indirect immunofluorescence Nucleic acids research Medium 9705521
2005 Within the yeast Ski2-Ski3-Ski8 complex, Ski3p serves as a scaffold: its C-terminus interacts with Ski8p and its sub-C-terminus interacts with Ski2p, while no direct interaction between Ski2p and Ski8p was detected. Ski7p interacts with the Ski complex via Ski8p and Ski3p. Mutating conserved DEVH helicase motif residues in Ski2p abolishes its enzymatic activity but does not disrupt its interaction with Ski7p, indicating helicase activity is dispensable for complex assembly. Directed yeast two-hybrid; co-immunoprecipitation; in vivo functional assays with helicase-dead Ski2p mutants RNA (New York, N.Y.) High 16043509
2011 Crystal structure of the 113 kDa helicase region of S. cerevisiae Ski2 at 2.4 Å resolution reveals an overall architecture similar to Mtr4, with a core DExH region and an extended insertion domain. The insertion domain is not required for Ski2-Ski3-Ski8 complex formation but instead functions as an RNA-binding domain with broad substrate specificity, binding both single-stranded and double-stranded RNAs. A zinc-binding site maintains the β-barrel and helical stalk as a single structural unit. The β-barrel lacks a KOW motif (unlike Mtr4). X-ray crystallography at 2.4 Å; in vitro RNA-binding assays; deletion constructs for complex formation RNA (New York, N.Y.) High 22114319
2016 Cryo-EM structure of an endogenous ribosome-Ski2-Ski3-Ski8 complex shows that the Ski complex directly associates with 80S ribosomes presenting a short mRNA 3' overhang. Ribosome binding displaces the autoinhibitory domain of Ski2, positioning it in an open conformation near the ribosomal mRNA entry tunnel. The mRNA 3' overhang is threaded directly from the small ribosomal subunit into the helicase channel of Ski2, primed for exosome-mediated 3'-5' degradation. Cryo-electron microscopy of endogenous complex; structural analysis at 4 Å (core) to ~10 Å (flexible regions) Science (New York, N.Y.) High 27980209
2018 Human Ski2 (SKIC2) and the RNA exosome complex mediate degradation of HBV HBx mRNA. IL-1β induces expression of ATF3 transcription factor, which binds to a CRE sequence in the Ski2 promoter and drives Ski2 transcription, leading to increased HBx mRNA degradation. HBx protein itself also induces Ski2 expression. Promoter-reporter assays; ChIP for ATF3 binding to Ski2 promoter; siRNA knockdown; mRNA stability assays Biochemical and biophysical research communications Medium 30055801

Source papers

Stage 0 corpus · 25 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1998 The 3' to 5' degradation of yeast mRNAs is a general mechanism for mRNA turnover that requires the SKI2 DEVH box protein and 3' to 5' exonucleases of the exosome complex. The EMBO journal 545 9482746
2016 The cryo-EM structure of a ribosome-Ski2-Ski3-Ski8 helicase complex. Science (New York, N.Y.) 95 27980209
1995 Synthetic lethality of sep1 (xrn1) ski2 and sep1 (xrn1) ski3 mutants of Saccharomyces cerevisiae is independent of killer virus and suggests a general role for these genes in translation control. Molecular and cellular biology 82 7739552
2012 Ski2-like RNA helicase structures: common themes and complex assemblies. RNA biology 72 22995828
2011 The crystal structure of S. cerevisiae Ski2, a DExH helicase associated with the cytoplasmic functions of the exosome. RNA (New York, N.Y.) 64 22114319
1995 Human helicase gene SKI2W in the HLA class III region exhibits striking structural similarities to the yeast antiviral gene SKI2 and to the human gene KIAA0052: emergence of a new gene family. Nucleic acids research 50 7610041
2005 Domain interactions within the Ski2/3/8 complex and between the Ski complex and Ski7p. RNA (New York, N.Y.) 48 16043509
1998 The human DEVH-box protein Ski2w from the HLA is localized in nucleoli and ribosomes. Nucleic acids research 35 9705521
1995 Identification and characterization of a human cDNA homologous to yeast SKI2. Genomics 34 7759100
1998 Four ubiquitously expressed genes, RD (D6S45)-SKI2W (SKIV2L)-DOM3Z-RP1 (D6S60E), are present between complement component genes factor B and C4 in the class III region of the HLA. Genomics 28 9799600
2020 RNA processing machineries in Archaea: the 5'-3' exoribonuclease aRNase J of the β-CASP family is engaged specifically with the helicase ASH-Ski2 and the 3'-5' exoribonucleolytic RNA exosome machinery. Nucleic acids research 20 32030412
2019 Molecular Mechanism Underlying Inhibition of Intrinsic ATPase Activity in a Ski2-like RNA Helicase. Structure (London, England : 1993) 15 31859026
1997 Identification of gene encoding a putative RNA-helicase, homologous to SKI2, in chromosome VII of Saccharomyces cerevisiae. Yeast (Chichester, England) 15 9133744
2018 IL-1β/ATF3-mediated induction of Ski2 expression enhances hepatitis B virus x mRNA degradation. Biochemical and biophysical research communications 13 30055801
2001 The Drosophila gene twister, an orthologue of the yeast helicase SKI2, is differentially expressed during development. Mechanisms of development 11 11472843
2000 Identification and characterization of a bidirectional promoter from the intergenic region between the human DDX13 and RD genes. Molecules and cells 10 10774746
2001 Features of the two gene pairs RD-SKI2W and DOM3Z-RP1 located between complement component genes factor B and C4 at the MHC class III region. Frontiers in bioscience : a journal and virtual library 9 11487501
2024 Tracing Allostery in the Spliceosome Ski2-like RNA Helicase Brr2. The journal of physical chemistry letters 8 38517341
2015 The Ski2-family helicase Obelus regulates Crumbs alternative splicing and cell polarity. The Journal of cell biology 5 26644515
2024 Evolutionary and functional insights into the Ski2-like helicase family in Archaea: a comparison of Thermococcales ASH-Ski2 and Hel308 activities. NAR genomics and bioinformatics 4 38500564
2022 The RNA helicase Ski2 in the fungal pathogen Cryptococcus neoformans highlights key roles in azoles resistance and stress tolerance. Medical mycology 4 36240494
1997 Genomic organization of the human DDX13 gene located between RD and RP1 in the class III MHC complex. Molecules and cells 4 9264031
2021 Long-range allostery mediates cooperative adenine nucleotide binding by the Ski2-like RNA helicase Brr2. The Journal of biological chemistry 3 34048711
2026 Ski2-like helicase ASCC3 unwinds DNA upon fork stalling to control replication stress responses. Cell reports 1 41785087
2025 The Ski2 helicase ASCC3 unwinds DNA upon fork stalling to control replication stress responses. bioRxiv : the preprint server for biology 0 40777259

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