SRP40 (YKR092C) is a small (406-residue, ~41 kDa), highly acidic (pI ~3.9), serine-rich (~49% Ser) nucleolar protein of Saccharomyces cerevisiae, and is the budding-yeast homolog of the vertebrate nucleolar phosphoprotein Nopp140 (its C-terminal SRP40_C domain is ~59% identical to the Nopp140 C-terminus). The protein is almost entirely intrinsically disordered, built from serine-rich low-complexity tracts interspersed with acidic (Asp/Glu) and basic (Lys/Arg) charge clusters, plus the single conserved folded C-terminal module; it carries no recognizable catalytic motif. Like Nopp140, it is a casein kinase II phosphoprotein (though phosphorylated to a lesser extent than the vertebrate protein) and is additionally serine- pyrophosphorylated by the inositol pyrophosphate 5-IP7. Srp40p localizes to the nucleolus and is proposed to act as a chaperone of small nucleolar ribonucleoprotein particles (snoRNPs) that mediate rRNA maturation, with a particular genetic link to the stability of box H/ACA snoRNAs; rat Nopp140 can functionally substitute for it. The gene is nonessential but dosage-sensitive: both deletion and overexpression impair growth. Its name ("Suppressor of RNA Polymerase") derives from its original isolation as a weak extragenic suppressor of a mutation in the AC40 subunit shared by RNA polymerases I and III, and does not denote a signal-recognition-particle function.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005730 nucleolus | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic (IBA) nucleolar localization, concordant with the direct yeast experimental evidence and with the Nopp140/SRP40 family being nucleolar. Accept as a core cellular-component annotation. Supporting Evidence: PMID:8702624 SRP40 localizes to the yeast nucleolus |
| GO:0005654 nucleoplasm | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Phylogenetically inferred nucleoplasmic localization. Nopp140/Treacle-family members do distribute to the nucleoplasm and coiled/Cajal bodies in addition to the nucleolus, so this is plausible, but the direct yeast evidence is for the nucleolus. Keep as a secondary, non-core location. |
| GO:0005730 nucleolus | IEA GO_REF:0000117 | ACCEPT | Summary: Electronic (ARBA) nucleolar localization; redundant with, and consistent with, the direct IDA and phylogenetic IBA nucleolus annotations. Accept. Supporting Evidence: PMID:8702624 SRP40 localizes to the yeast nucleolus |
| GO:0003674 molecular_function | ND GO_REF:0000015 | ACCEPT | Summary: Root molecular_function with ND (no data). This is an honest reflection of the state of knowledge: no specific molecular activity has been experimentally assigned to this disordered nucleolar protein, and none can be inferred from sequence (no catalytic motif; only the non-enzymatic C-terminal SRP40_C module). Accept rather than inventing an MF term; the genuine molecular-function gap is recorded in knowledge_gaps. |
| GO:0005730 nucleolus | IDA PMID:8702624 Comparison of the rat nucleolar protein nopp140 with its yea... | ACCEPT | Summary: Direct experimental (IDA) localization of Srp40p to the yeast nucleolus. This is the best-supported, core cellular-component annotation for the gene. Supporting Evidence: PMID:8702624 SRP40 localizes to the yeast nucleolus |
| GO:0006913 nucleocytoplasmic transport | ISS PMID:8702624 Comparison of the rat nucleolar protein nopp140 with its yea... | KEEP AS NON CORE | Summary: ISS annotation transferred from the rat ortholog Nopp140 (UniProtKB:P41777). Nopp140 shuttles between the nucleolus and cytoplasm and binds nuclear localization signals, and was proposed to chaperone ribosome biogenesis on that basis; the transport/shuttling activity, however, is a vertebrate-Nopp140 property and has NOT been directly demonstrated for yeast Srp40p, and the source paper itself notes yeast/vertebrate disparities in nucleolar dynamics. The better-supported functional role of yeast Srp40p is nucleolar snoRNP chaperoning within ribosome biogenesis (PMID:12700234), not transport per se. Retain as a non-core, ortholog-inferred process rather than removing an ISS annotation made by a curator from a selected ortholog. Supporting Evidence: PMID:8702624 its nuclear localization signal binding capacity, and its shuttling between the nucleolus and the cytoplasm, Nopp140 was proposed to function as a chaperone in ribosome biogenesis |
| GO:0042254 ribosome biogenesis | IGI PMID:12700234 Genetic interaction between a chaperone of small nucleolar r... | NEW | Summary: Proposed new annotation (not currently in GOA). Srp40p is a nucleolar protein proposed to chaperone the snoRNPs required for rRNA maturation, and its genetic depletion specifically destabilizes box H/ACA snoRNAs; rat Nopp140 restores box H/ACA snoRNA stability, confirming it as the functional Nopp140 homolog. This is the best-supported biological process for the gene and is captured as a core function. Evidence is genetic/homology-based (a proposal), so the underlying molecular activity remains a knowledge gap. Supporting Evidence: PMID:12700234 Srp40p is a nonessential yeast nucleolar protein proposed to function as a chaperone for over 100 small nucleolar ribonucleoprotein particles that are required for rRNA maturation. |
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Download this section (compressed HTML)Q: Does Srp40p bind snoRNAs (particularly box H/ACA snoRNAs) or snoRNP proteins directly, and does it possess measurable RNA-chaperone (annealing/remodeling) or RNP-assembly activity in vitro?
Q: At which step of ribosome biogenesis does Srp40p act, and does its loss primarily affect box H/ACA snoRNP assembly, stability, localization, or recycling?
Q: What accounts for the dual dosage sensitivity (both deletion and overexpression are deleterious), and which factors buffer srp40-delta to keep the gene nonessential?
Q: Do the CK2 phosphorylation and 5-IP7 serine pyrophosphorylation of Srp40p regulate its snoRNP-associated function, and can specific phospho-sites be linked to the growth or box H/ACA snoRNA phenotypes?
Experiment: In vitro RNA-binding and RNA-chaperone assays (EMSA, filter binding, FRET-based annealing/strand-displacement) using recombinant Srp40p and candidate box H/ACA snoRNAs and snoRNP components, with the disordered N-terminus and the SRP40_C domain tested separately.
Experiment: Endogenous affinity purification / proximity labeling (e.g. BioID or AP-MS) plus CLIP-seq of tagged Srp40p to define its direct protein and RNA partners in the nucleolus and to test the snoRNP-chaperone model in vivo.
Experiment: Systematic genetic analysis (synthetic-lethal / dosage screens beyond the known shm2 ade3 interaction) and phospho-site mutant series (CK2 and 5-IP7 pyrophosphorylation sites) scored for growth, box H/ACA snoRNA levels, and rRNA processing, to connect Srp40p's PTMs and partners to its cellular role.
What is not known — curated, literature-grounded statements of the open unknowns (the inverse of core functions).
Gap: The specific molecular activity of Srp40p and the precise step in ribosome biogenesis at which it acts are unknown. Whether it directly chaperones/assembles snoRNPs, stabilizes box H/ACA snoRNAs, or contributes indirectly (e.g. through its highly phosphorylated, acidic, disordered tracts) is undetermined, as is the reason the gene is simultaneously nonessential and dosage-sensitive (toxic when either deleted or overexpressed).
OPEN BIOLOGYONTOLOGY MF_DARK
What is known: Firmly established: Srp40p is the yeast Nopp140 homolog (SRP40_C domain ~59% identical to Nopp140's C-terminus); it is a ~41 kDa, acidic (pI ~3.9), ~49%-serine, almost fully intrinsically disordered nucleolar protein with no catalytic motif; it is CK2-phosphorylated and 5-IP7 serine-pyrophosphorylated; it localizes to the nucleolus (IDA); it is nonessential but its deletion and overexpression both impair growth; its genetic depletion specifically destabilizes box H/ACA snoRNAs; and rat Nopp140 functionally complements srp40-delta.
Significance: Defining the activity of this tractable, conserved nucleolar chaperone would illuminate how the Nopp140/Treacle family (implicated in human ribosomopathies) contributes to snoRNP function and rRNA maturation, and would provide an experimental anchor for a class of disordered nucleolar proteins that GO cannot currently describe at the molecular-function level.
What would resolve it: Biochemical reconstitution of Srp40p RNA/snoRNP-chaperone activity; interactome/ CLIP mapping of its snoRNP (especially box H/ACA) partners in vivo; genetic dissection of the redundancy/buffering that renders it nonessential and of the basis of overexpression toxicity; phospho-site (CK2 / 5-IP7) separation-of-function alleles to connect its unusual PTMs to the growth and box H/ACA phenotypes.
Provenance (the field's own admissions):
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