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Showing PRPF40A — PRP40 is a alias.

PRPF40A

Pre-mRNA-processing factor 40 homolog A · UniProt O75400

Length
957 aa
Mass
108.8 kDa
Annotated
2026-06-10
45 papers in source corpus 9 papers cited in narrative 8 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 5/5 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

PRPF40A is a pre-mRNA splicing factor that uses tandem WW domains to read proline-rich motifs in early spliceosome components and promote alternative exon inclusion (PMID:38719828, PMID:38943321). Structural work established that the first WW domain folds into an antiparallel triple-stranded beta-sheet that engages PL, PP, and PR motifs through its XP and XP2 grooves (PMID:16463264, PMID:16472085), and that the two WW domains cooperate to bind a high-affinity SF1 peptide by sandwiching a tryptophan between two proline residues; an N-terminal autoinhibitory proline-rich motif folds back onto the WW tandem to act as a selectivity filter favoring bona fide partners SF1 and SF3A1 (PMID:38719828). Functionally, PRPF40A acts predominantly as an activator of cassette exon inclusion, with strong preference for exons flanked by short GC-rich introns and for microexons, where its dependence is graded by exon size, and it operates within a splicing-factor network including SRRM2, SON, SRRM4, PCBP1/2, TRA2B, and SRSF2 (PMID:38943321, PMID:39389624). It localizes to nuclear speckles and can sequester binding partners such as N-WASP in the nucleus, thereby restraining their cytoplasmic activity (PMID:14697212). Polyglutamine-expanded huntingtin cooperatively engages the WW tandem via its proline-rich region and mislocalizes PRPF40A to the cytosol, reducing pre-mRNA splicing efficiency (PMID:21566141).

Mechanistic history

Synthesis pass · year-by-year structured walk · 6 steps
  1. 2004 Medium

    Established that PRPF40A is a nuclear-speckle protein capable of controlling a partner's cytoplasmic activity by nuclear retention, first linking it to spatial regulation of interacting proteins.

    Evidence Overexpression, fluorescence localization, and actin microspike assays in COS7 cells

    PMID:14697212

    Open questions at the time
    • No direct binding interface defined for N-WASP
    • Relationship between N-WASP trapping and splicing function not addressed
  2. 2005 Medium

    Showed PRPF40A engages additional nuclear-matrix proline-rich partners (NAKAP) through its WW domains and is recruited into Huntington's disease nuclear aggregates, extending its interaction repertoire beyond splicing.

    Evidence Yeast two-hybrid, in vitro binding, deletion mapping, fractionation, and co-IP from human brain

    PMID:16391387

    Open questions at the time
    • Functional consequence of NAKAP binding unknown
    • Does not connect aggregate localization to splicing defects
  3. 2006 Medium

    Resolved how the first WW domain recognizes ligands, defining the structural basis (XP and XP2 grooves) for proline-rich motif binding by PRPF40A.

    Evidence NMR solution structure, HSQC ligand titration, and GST pulldown

    PMID:16463264 PMID:16472085

    Open questions at the time
    • Single WW domain in isolation; tandem cooperativity not addressed
    • Low affinity (248 µM) leaves physiological partner specificity open
  4. 2011 Medium

    Provided a disease mechanism: polyQ-huntingtin cooperatively binds the WW tandem and relocalizes PRPF40A to the cytosol, mechanistically linking its sequestration to impaired splicing.

    Evidence NMR structural analysis, pre-mRNA splicing efficiency assay, and subcellular localization

    PMID:21566141

    Open questions at the time
    • Which endogenous splicing targets are affected not identified
    • In vivo neuronal relevance not established
  5. 2024 High

    Defined the tandem-WW solution architecture and an intramolecular autoinhibitory selectivity filter, explaining how PRPF40A achieves high-affinity, selective binding to spliceosomal partners SF1 and SF3A1.

    Evidence NMR, SAXS, ITC, mutagenesis, and co-IP in cells

    PMID:38719828

    Open questions at the time
    • How autoinhibition is relieved in vivo not defined
    • Structural state within assembled spliceosome unknown
  6. 2024 Medium

    Demonstrated PRPF40A is a transcriptome-wide activator of cassette exon and microexon inclusion biased toward short GC-rich introns and nuclear speckles, embedding it in a defined splicing-regulatory network with cellular phenotypes on viability and differentiation.

    Evidence shRNA/siRNA knockdown, RNA-seq splicing analysis, rescue and viability assays in HL-60 and N2A cells

    PMID:38943321 PMID:39389624

    Open questions at the time
    • Direct RNA or factor contacts driving exon selection not mapped
    • Mechanism of homeostatic Luc7l poison-exon cross-regulation unresolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • Whether human PRPF40A makes direct, regulated contacts with RNA polymerase II or the U1 snRNP during co-transcriptional splicing remains undefined.
  • No direct evidence for human PRPF40A–pol II interaction
  • Extent of co-transcriptional vs post-transcriptional action in human cells unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0003723 RNA binding 2 GO:0140110 transcription regulator activity 2 GO:0060090 molecular adaptor activity 1
Localization
GO:0005634 nucleus 2
Pathway
R-HSA-8953854 Metabolism of RNA 3
Partners
HTTN-WASPSF1SF3A1SONSRRM2SRRM4TRA2B

Evidence

Reading pass · 8 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2011 Polyglutamine-expanded huntingtin sequesters HYPA/FBP11 (PRPF40A) to the cytosolic location, significantly reducing pre-mRNA splicing efficiency. NMR structural analysis showed that the proline-rich region (PRR) of huntingtin cooperatively interacts with the tandem WW domains of HYPA through a domain chaperoning effect of WW1 on WW2. NMR structural analysis, pre-mRNA splicing efficiency assay, subcellular localization experiments The Journal of biological chemistry Medium 21566141
2004 FBP11 (PRPF40A) inhibits N-WASP-dependent microspike formation by trapping N-WASP in the nucleus. Endogenous FBP11 localizes to nuclear speckles, and co-expression with N-WASP causes co-localization in the nucleus, preventing N-WASP from acting in the cytoplasm. Transient overexpression, subcellular localization by fluorescence microscopy, actin microspike formation assay in COS7 cells Biochemical and biophysical research communications Medium 14697212
2005 The nuclear matrix protein NAKAP interacts with HYPA/FBP11 (PRPF40A) via a proline-rich domain in NAKAP binding to a WW domain of HYPA. NAKAP and HypA co-localize within the nucleus, co-purify with the nuclear matrix, and are components of nuclear aggregates in Huntington's disease neurons. Yeast two-hybrid screen, in vitro binding assay, deletion mapping, subcellular fractionation, co-immunoprecipitation from human brain tissue Neuromolecular medicine Medium 16391387
2006 The first WW domain of FBP11/HYPA (PRPF40A) adopts an antiparallel triple-stranded beta-sheet structure. It binds proline-rich sequences containing PL, PP, and PR motifs via both XP and XP2 grooves, with the XP2 groove being functionally important for ligand recognition. Dissociation constant for a PL motif peptide was 248 ± 27 µM. NMR solution structure determination, ligand titration by 1H-15N HSQC NMR, GST pulldown binding assay Proteins Medium 16463264 16472085
2024 PRPF40A tandem WW domains adopt a defined solution structure characterized by NMR/SAXS. Both WW domains cooperate to bind a high-affinity SF1 peptide, enabling tryptophan sandwiching by two proline residues. An N-terminal proline-rich motif of PRPF40A mediates intramolecular autoinhibitory interactions with the WW tandem, acting as a selectivity filter for high-affinity proline-rich bona fide binding partners (SF1 and SF3A1). This was validated by NMR, ITC, mutagenesis, and immunoprecipitation in cells. NMR spectroscopy, SAXS, ITC, mutagenesis, co-immunoprecipitation in cells Nature communications High 38719828
2024 PRPF40A acts predominantly as an activator of cassette exon inclusion, particularly of exons flanked by short GC-rich introns that tend to localize to nuclear speckles. PRPF40A knockdown in HL-60 cells caused increased cell death, decreased proliferation, and slight myeloid differentiation phenotype. Cell death but not proliferation was rescued by overexpression of paralog PRPF40B. PRPF40A functions in a network with SRRM2, SON, PCBP1/2, TRA2B, and SRSF2. shRNA knockdown, transcriptomic analysis (RNA-seq), overexpression rescue experiments, cell viability and proliferation assays Nucleic acids research Medium 38943321
2024 PRPF40A is globally required for microexon splicing in mouse neuroblastoma cells, with a graded dependence on exon size (greater dependence for smaller exons). PRPF40A co-regulates microexons with SRRM4. PRPF40A knockdown also causes increased productive splicing of its spliceosomal binding partner Luc7l by skipping a 'poison exon', suggesting homeostatic cross-regulation between coupled spliceosomal components. siRNA knockdown, RNA-seq, splicing analysis in N2A cells RNA (New York, N.Y.) Medium 39389624
2025 In yeast, Prp40 (ortholog of PRPF40A) interacts with RNA polymerase II through multiple domains, and this interaction does not require the CTD of pol II. While yeast Prp40 is stably associated with U1 snRNP and is the primary mediator of U1 snRNP-pol II interaction, its human homologs PRPF40A and PRPF40B are alternative splicing factors not integral to U1 snRNP. Co-immunoprecipitation, domain deletion analysis, yeast genetic experiments bioRxivpreprint Low bio_10.1101_2025.08.28.672894

Source papers

Stage 0 corpus · 45 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1995 The petunia MADS box gene FBP11 determines ovule identity. The Plant cell 271 8535139
2001 Requirement of nickel metabolism proteins HypA and HypB for full activity of both hydrogenase and urease in Helicobacter pylori. Molecular microbiology 156 11123699
2002 Network of hydrogenase maturation in Escherichia coli: role of accessory proteins HypA and HybF. Journal of bacteriology 79 12081959
1996 The Agaricus bisporus hypA gene encodes a hydrophobin and specifically accumulates in peel tissue of mushroom caps during fruit body development. Journal of molecular biology 73 8632464
2009 Structure of a nickel chaperone, HypA, from Helicobacter pylori reveals two distinct metal binding sites. Journal of the American Chemical Society 65 19621959
2017 COL1A1, PRPF40A, and UCP2 correlate with hypoxia markers in non-small cell lung cancer. Journal of cancer research and clinical oncology 57 28258342
2005 Escherichia coli HypA is a zinc metalloprotein with a weak affinity for nickel. Journal of bacteriology 55 15995183
2011 Metallo-GTPase HypB from Helicobacter pylori and its interaction with nickel chaperone protein HypA. The Journal of biological chemistry 47 22179820
2010 Communication between the zinc and nickel sites in dimeric HypA: metal recognition and pH sensing. Journal of the American Chemical Society 46 20662514
2006 Mutagenesis of hydrogenase accessory genes of Synechocystis sp. PCC 6803. Additional homologues of hypA and hypB are not active in hydrogenase maturation. The FEBS journal 42 16972939
2016 Mechanism of Selective Nickel Transfer from HypB to HypA, Escherichia coli [NiFe]-Hydrogenase Accessory Proteins. Biochemistry 39 27951644
2007 Interaction between the Helicobacter pylori accessory proteins HypA and UreE is needed for urease maturation. Microbiology (Reading, England) 39 17464061
2013 Metal transfer within the Escherichia coli HypB-HypA complex of hydrogenase accessory proteins. Biochemistry 35 23899293
2011 Protein interactions and localization of the Escherichia coli accessory protein HypA during nickel insertion to [NiFe] hydrogenase. The Journal of biological chemistry 35 22016389
2004 Aspergillus nidulans hypA regulates morphogenesis through the secretion pathway. Fungal genetics and biology : FG & B 35 14643261
2014 Nickel translocation between metallochaperones HypA and UreE in Helicobacter pylori. Metallomics : integrated biometal science 29 25010720
2012 The Arthroderma benhamiae hydrophobin HypA mediates hydrophobicity and influences recognition by human immune effector cells. Eukaryotic cell 29 22408226
2012 Helicobacter pylori hydrogenase accessory protein HypA and urease accessory protein UreG compete with each other for UreE recognition. Biochimica et biophysica acta 26 22698670
2011 Interaction with polyglutamine-expanded huntingtin alters cellular distribution and RNA processing of huntingtin yeast two-hybrid protein A (HYPA). The Journal of biological chemistry 26 21566141
2007 A dynamic Zn site in Helicobacter pylori HypA: a potential mechanism for metal-specific protein activity. Journal of the American Chemical Society 25 17199266
1994 Nucleotide sequences of two hydrogenase-related genes (hypA and hypB) from Bradyrhizobium japonicum, one of which (hypB) encodes an extremely histidine-rich region and guanine nucleotide-binding domains. Biochimica et biophysica acta 21 8305450
2004 FBP11 regulates nuclear localization of N-WASP and inhibits N-WASP-dependent microspike formation. Biochemical and biophysical research communications 20 14697212
2006 Solution structure and binding specificity of FBP11/HYPA WW domain as Group-II/III. Proteins 19 16463264
2015 Dynamic HypA zinc site is essential for acid viability and proper urease maturation in Helicobacter pylori. Metallomics : integrated biometal science 18 25608738
2017 Nickel Ligation of the N-Terminal Amine of HypA Is Required for Urease Maturation in Helicobacter pylori. Biochemistry 16 28177601
2017 Structure-function analyses of metal-binding sites of HypA reveal residues important for hydrogenase maturation in Helicobacter pylori. PloS one 16 28809946
2018 Structure and dynamics of Helicobacter pylori nickel-chaperone HypA: an integrated approach using NMR spectroscopy, functional assays and computational tools. Journal of biological inorganic chemistry : JBIC : a publication of the Society of Biological Inorganic Chemistry 15 30264175
2018 The Helicobacter pylori HypA·UreE2 Complex Contains a Novel High-Affinity Ni(II)-Binding Site. Biochemistry 14 29708738
2005 Association of HYPA haplotype in the mannose-binding lectin gene-2 with Behçet's disease. Tissue antigens 12 15730518
2005 Interaction of the nuclear matrix protein NAKAP with HypA and huntingtin: implications for nuclear toxicity in Huntington's disease pathogenesis. Neuromolecular medicine 11 16391387
2019 Bimodal Nickel-Binding Site on Escherichia coli [NiFe]-Hydrogenase Metallochaperone HypA. Inorganic chemistry 10 31273981
2013 The zinc-binding fragment of HypA from Helicobacter pylori: a tempting site also for nickel ions. Dalton transactions (Cambridge, England : 2003) 10 23338727
2019 The Metallochaperone Encoding Gene hypA Is Widely Distributed among Pathogenic Aeromonas spp. and Its Expression Is Increased under Acidic pH and within Macrophages. Microorganisms 9 31581740
2024 PRPF40A induces inclusion of exons in GC-rich regions important for human myeloid cell differentiation. Nucleic acids research 7 38943321
2015 Specificity of the Zn(2+), Cd(2+) and Ni(2+) ion binding sites in the loop domain of the HypA protein. Dalton transactions (Cambridge, England : 2003) 7 25945782
2023 The structure of the high-affinity nickel-binding site in the Ni,Zn-HypA•UreE2 complex. Metallomics : integrated biometal science 6 36638839
2006 Expression and purification of active WW domains of FBP11/HYPA and FBP28/CA150. Protein and peptide letters 6 16472085
2024 Intramolecular autoinhibition regulates the selectivity of PRPF40A tandem WW domains for proline-rich motifs. Nature communications 5 38719828
1998 Rhizobium leguminosarum bv. viciae hypA gene is specifically expressed in pea (Pisum sativum) bacteroids and required for hydrogenase activity and processing. FEMS microbiology letters 5 9868773
2024 Conserved role for spliceosomal component PRPF40A in microexon splicing. RNA (New York, N.Y.) 3 39389624
2013 Mannose-binding lectin genetic analysis: possible protective role of the HYPA haplotype in the development of recurrent urinary tract infections in men. International journal of infectious diseases : IJID : official publication of the International Society for Infectious Diseases 3 24321858
2026 Dose-dependent biphasic effect of environmental UVA on stem cell function through PRPF40A, TGF-β1, NFATc1 signaling. Journal of photochemistry and photobiology. B, Biology 0 41950867
2026 The HypA and HypB metallochaperones from Methanococcus maripaludis have unique metal-binding properties and a distinct nickel transfer mechanism. The Journal of biological chemistry 0 42001940
2026 Nickel binding shifts Helicobacter pylori HypA toward compact conformations. Journal of inorganic biochemistry 0 42217269
2024 Conserved role for spliceosomal component PRPF40A in microexon splicing. bioRxiv : the preprint server for biology 0 39386728

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