PRPF31 Protein

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PRPF31 Protein

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PRPF31 Protein — Pre-mRNA Processing Factor 31

<div class="infobox infobox-protein">
<table>
<tr><th colspan="2" style="background:#e8f4f8; text-align:center; font-size:1.1em;">PRPF31 Protein (Prp31)</th></tr>
<tr><td><strong>Protein Name</strong></td><td>Pre-mRNA Processing Factor 31</td></tr>
<tr><td><strong>Gene</strong></td><td>[PRPF31](/genes/prpf31)</td></tr>
<tr><td><strong>UniProt ID</strong></td><td>[O94973](https://www.uniprot.org/uniprotkb/O94973/entry)</td></tr>
<tr><td><strong>PDB ID</strong></td><td>6EXN, 6QDV</td></tr>
<tr><td><strong>Molecular Weight</strong></td><td>55.6 kDa</td></tr>
<tr><td><strong>Subcellular Localization</strong></td><td>Nucleus (spliceosome)</td></tr>
<tr><td><strong>Protein Family</strong></td><td>Prp31 family (spliceosomal protein family)</td></tr>
<tr><td><strong>Tissue Expression</strong></td><td>Ubiquitous; high in retina, brain, heart</td></tr>
<tr><td><strong>Function</strong></td><td>U4/U6.U5 tri-snRNP assembly, spliceosome activation</td></tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">1 edges</a></td>
</tr>
</table>
</div>

Overview

...

PRPF31 Protein — Pre-mRNA Processing Factor 31

<div class="infobox infobox-protein">
<table>
<tr><th colspan="2" style="background:#e8f4f8; text-align:center; font-size:1.1em;">PRPF31 Protein (Prp31)</th></tr>
<tr><td><strong>Protein Name</strong></td><td>Pre-mRNA Processing Factor 31</td></tr>
<tr><td><strong>Gene</strong></td><td>[PRPF31](/genes/prpf31)</td></tr>
<tr><td><strong>UniProt ID</strong></td><td>[O94973](https://www.uniprot.org/uniprotkb/O94973/entry)</td></tr>
<tr><td><strong>PDB ID</strong></td><td>6EXN, 6QDV</td></tr>
<tr><td><strong>Molecular Weight</strong></td><td>55.6 kDa</td></tr>
<tr><td><strong>Subcellular Localization</strong></td><td>Nucleus (spliceosome)</td></tr>
<tr><td><strong>Protein Family</strong></td><td>Prp31 family (spliceosomal protein family)</td></tr>
<tr><td><strong>Tissue Expression</strong></td><td>Ubiquitous; high in retina, brain, heart</td></tr>
<tr><td><strong>Function</strong></td><td>U4/U6.U5 tri-snRNP assembly, spliceosome activation</td></tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">1 edges</a></td>
</tr>
</table>
</div>

Overview

PRPF31 (Pre-mRNA Processing Factor 31), also known as Prp31, is an essential spliceosomal protein that plays a critical role in the assembly and activation of the U4/U6.U5 tri-snRNP complex. As a component of the spliceosome, PRPF31 is required for the removal of introns from pre-mRNA in all eukaryotes, making it fundamental to gene expression. The protein is ubiquitously expressed with particularly high levels in the retina and brain, reflecting the high demand for RNA processing in these tissues.

Mutations in the PRPF31 gene were first identified as a major cause of retinitis pigmentosa (RP), a hereditary retinal degeneration that leads to progressive vision loss. This discovery established PRPF31 as a disease-relevant protein and stimulated research into its functions beyond basic RNA splicing. More recently, alterations in PRPF31 expression and function have been implicated in neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis (ALS), linking spliceosomal dysfunction to broader neurological pathology [@kondo2015; @yang2019].

This comprehensive page provides detailed coverage of PRPF31's molecular structure, its normal functions in RNA processing and neuronal biology, its involvement in retinal and neurodegenerative diseases, and emerging therapeutic strategies.

Structure and Molecular Architecture

PRPF31 is a protein of approximately 499 amino acids with a molecular weight of about 55.6 kDa. The protein adopts a distinctive fold that enables its specific interactions within the spliceosome.

Domain Organization

The structure of PRPF31 consists of several functional regions:

N-terminal Domain:

Contains the NOP domain (NOP56/58 interaction domain)
Mediates interaction with NOP56 and NOP58 in the box C/D snoRNP-like complex
Required for proper subcellular localization within the nucleus

Central Region:

Contains the MEA (M-dependent Exon Analyzer) domain
Involved in protein-protein interactions within the spliceosome
Contains the main interaction surfaces for other spliceosomal proteins

C-terminal Region:

Contains the C-terminal domain (CTD)
Important for spliceosomal targeting
Contains residues critical for tri-snRNP integration

Three-Dimensional Structure

High-resolution crystal structures of PRPF31 have revealed important architectural features:

Overall Fold:

Composed of multiple α-helices and β-sheets
Forms a compact globular domain
Contains a deep binding pocket for protein interactions

Interaction Interfaces:

Multiple surfaces for binding other spliceosomal proteins
The N-terminal region interacts with NOP56/NOP58
The central region contacts Prp4 and other tri-snRNP proteins

Post-translational Modifications

PRPF31 undergoes several regulatory modifications:

Phosphorylation:

Serine/threonine phosphorylation detected
May regulate spliceosome dynamics during the splicing cycle
Potential regulatory role in catalytic steps

Methylation:

Arginine methylation documented
May affect protein-protein interactions
Could regulate spliceosome assembly

Normal Function in RNA Processing

PRPF31 is an essential component of the spliceosome with specific functions in the assembly and activation of the U4/U6.U5 tri-snRNP.

The Spliceosome and Tri-snRNP Assembly

The spliceosome is a large ribonucleoprotein complex that performs pre-mRNA splicing. The U4/U6.U5 tri-snRNP represents a key intermediate in spliceosome assembly:

Tri-snRNP Composition:

U4 small nuclear RNA (snRNA)
U6 snRNA
U5 snRNA
Associated proteins including PRPF31, PRPF4, PRPF6, PRPF3, and others

Assembly Pathway:

The tri-snRNP forms independently in the nucleus
PRPF31 is critical for proper tri-snRNP assembly
The assembled tri-snRNP then joins the spliceosome

PRPF31's Specific Role

PRPF31 performs several essential functions within the spliceosome:

U4/U6 snRNA Interactions:

Binds directly to U4 snRNA
Stabilizes the U4/U6 snRNA duplex
Required for proper U4/U6 base-pairing

Tri-snRNP Stability:

Contributes to the structural integrity of the tri-snRNP
Required for recruitment of the tri-snRNP to the spliceosome
Critical for the transition from early to activated spliceosome

Spliceosome Activation:

PRPF31 must be released for catalytic steps
The protein's displacement is part of spliceosome activation
Regulated by RNA helicases including BRR2

Alternative Splicing Regulation

Beyond its essential role in constitutive splicing, PRPF31 influences alternative splicing patterns:

Splicing Fidelity:

Proper PRPF31 function ensures accurate splice site selection
Mutations can lead to mis-splicing events
Important for tissue-specific splicing programs

Neuronal-Specific Splicing:

Neurons have complex alternative splicing requirements
PRPF31 contributes to neuronal-specific splice variants
Important for generating protein diversity in the nervous system

Role in the Nervous System

The high expression of PRPF31 in the brain and retina makes it particularly important for neuronal function and survival.

Retina and Photoreceptor Function

PRPF31 is highly expressed in photoreceptor cells of the retina, where its function is critical:

Photoreceptor Biology:

Photoreceptors have extremely high rates of transcription
Heavy demand for RNA processing and splicing
PRPF31 mutations cause photoreceptor degeneration

Phototransduction Genes:

Many phototransduction protein genes require specific splicing
PRPF31 dysfunction affects expression of essential photoreceptor proteins
Contributes to retinitis pigmentosa pathology

Brain and Neuronal Function

In the central nervous system, PRPF31 performs essential functions:

Neuronal Gene Expression:

Neurons rely heavily on regulated RNA processing
Alternative splicing generates protein diversity
PRPF31 contributes to neuronal-specific splicing programs

Synaptic Function:

Many synaptic proteins require proper splicing
PRPF31 dysfunction may affect synaptic protein isoforms
May contribute to synaptic dysfunction in disease

Glial Cells

PRPF31 also functions in glial cells:

Astrocyte Function:

Astrocytes have complex gene expression programs
PRPF31 supports proper RNA processing
Relevant to neuroimmune responses

Oligodendrocyte Biology:

Myelin gene expression requires proper splicing
PRPF31 important for oligodendrocyte function
May affect myelination processes

Role in Neurodegenerative Diseases

Dysregulation of PRPF31 has been implicated in several neurodegenerative diseases, expanding its relevance beyond retinal degeneration.

Retinitis Pigmentosa

PRPF31 mutations were first identified as a major cause of autosomal dominant retinitis pigmentosa (ADRP):

Genetics:

Over 100 pathogenic mutations identified
Dominant-negative mechanism proposed
Variable penetrance observed

Pathogenesis:

Photoreceptor degeneration leads to progressive vision loss
Night blindness as early symptom
Progressive peripheral vision loss leading to tunnel vision

Disease Mechanisms:

PRPF31 haploinsufficiency model
Dominant-negative effects of mutant proteins
Photosensitivity of photoreceptor cells

Alzheimer's Disease

Emerging evidence links PRPF31 to Alzheimer's disease:

Splicing Dysregulation:

Global changes in alternative splicing observed in AD brain
Specific splicing factor expression altered
PRPF31 expression changes documented

Pathological Links:

Splicing alterations affect APP and tau isoform expression
May contribute to disease-relevant protein changes
Splicing disruption as common feature

Research Findings:

Altered PRPF31 levels in AD models
Correlates with disease severity
Potential therapeutic target

Parkinson's Disease

PRPF31 connections to PD are emerging:

Splicing Changes:

Altered splicing patterns in PD brain
Expression changes in splicing factors
May affect dopaminergic neuron function

Potential Mechanisms:

Splicing of mitochondrial proteins affected
May influence protein quality control
Could impact alpha-synuclein processing

Amyotrophic Lateral Sclerosis (ALS)

Links between spliceosomal proteins and ALS have been established:

Splicing Factor Mutations:

Multiple splicing factors mutated in ALS
PRPF31 expression altered in some cases
General spliceosome dysfunction observed

Motor Neuron Vulnerability:

Motor neurons particularly dependent on splicing
High metabolic demand makes them vulnerable
Splicing disruption leads to cell death

Other Neurological Disorders

Huntington's Disease:

Splicing alterations documented
May involve spliceosomal proteins
Contributes to transcriptional dysfunction

Spinal Muscular Atrophy:

Related to SMN deficiency affecting snRNP assembly
Splicing broadly affected
Links to PRPF31 function

Therapeutic Strategies

Understanding PRPF31's role in disease has stimulated interest in therapeutic approaches:

Gene Therapy

Viral Delivery:

AAV vectors for gene delivery
Express wild-type PRPF31 in retina
Current approaches for retinitis pigmentosa

Gene Editing:

CRISPR-based approaches
Correct disease-causing mutations
Emerging therapeutic modality

Small Molecule Approaches

Spliceosome Modulators:

Modulate spliceosome function
Can restore proper splicing patterns
Challenge: achieving specificity

Splicing Modulation:

ASO-based approaches
Target specific splicing events
Currently in development

Antisense Oligonucleotides

ASO Therapy:

Single-stranded DNA oligonucleotides
Can restore proper splicing
Currently approved for other conditions

Applications:

Target mutant PRPF51 splicing
Modulate expression of splicing regulators
May be applicable to PRPF31-related diseases

Interaction Network

PRPF31 interacts with numerous proteins within the spliceosome:

Core Tri-snRNP Proteins

| Partner Protein | Interaction Type | Functional Consequence |
|-----------------|-------------------|------------------------|
| PRPF4 | Direct interaction | Tri-snRNP assembly |
| PRPF6 | Network interaction | Spliceosome scaffolding |
| PRPF3 | Direct interaction | U4/U6 stability |
| PRPF8 | Indirect via complex | Catalytic steps |

NOP56/NOP58 Complex

| Partner | Interaction | Function |
|---------|-------------|----------|
| NOP56 | Direct binding | Box C/D-related complex |
| NOP58 | Direct binding | snoRNP-like function |

Spliceosome Assembly Factors

| Factor | Interaction | Stage |
|--------|-------------|-------|
| PRPF19 | Network interaction | Catalytic steps |
| BRR2 | Regulation | Helicase activity |
| PRP4 | Direct interaction | Tri-snRNP recruitment |

Animal Models and Research Findings

Model Systems

Yeast:

Homologous protein Prp31 in S. cerevisiae
Essential for viability
Detailed mechanistic studies possible

Zebrafish:

Retinal development models
PRPF31 knockdown affects photoreceptors
Useful for drug screening

Mammalian Models:

Mouse models of RP
Conditional knockouts
Behavioral and histological analysis

Key Findings

Essential Function:

Complete knockout lethal
Partial loss causes specific defects
Different tissues show varying sensitivity

Disease Models:

PRPF31 mutations cause retinal degeneration
Splicing defects documented
Rescue by wild-type expression

Future Directions

Research Priorities

Structural Studies: High-resolution structure of PRPF31 in spliceosome

Disease Mechanisms: How mutations cause retinal degeneration

Therapeutic Development: Gene therapy and small molecule approaches

Biomarkers: Splicing signatures as disease biomarkers

Unresolved Questions

What determines tissue-specific vulnerability to PRPF31 mutations?
Can spliceosome function be safely modulated therapeutically?
What is the full extent of PRPF31's substrate specificity?
How do different mutations cause distinct phenotypes?

External Links

[UniProt: PRPF31 (O94973)](https://www.uniprot.org/uniprotkb/O94973/entry)
[RCSB PDB: PRPF31 Structures](https://www.rcsb.org/)
[NCBI Gene: PRPF31](https://www.ncbi.nlm.nih.gov/gene/55832)
[Homo sapiens Spliceosome Pathway (KEGG)](https://www.genome.jp/kegg/pathway/map03040)
[Retina International: RP Research](https://www.retina-international.org/)

References

[Litvak et al., The yeast Prp31 protein and U4/U6 snRNP assembly (Molecular and Cellular Biology, 2003)](https://doi.org/10.1128/MCB.23.7.2329-2339.2003) PMID: 12665571(https://pubmed.ncbi.nlm.nih.gov/12665571/)

[Carmel et al., Structural analysis of PRPF31 mutations in RP (Human Molecular Genetics, 2004)](https://doi.org/10.1093/hmg/ddh255) PMID: 15190012(https://pubmed.ncbi.nlm.nih.gov/15190012/)

[Will & Lührmann, Spliceosome structure and function (Current Opinion in Cell Biology, 1999)](https://doi.org/10.1016/S0955-0674(99)80010-6) PMID: 10395531(https://pubmed.ncbi.nlm.nih.gov/10395531/)

[Schneider et al., PRPF31 mutations in RP (Human Molecular Genetics, 2010)](https://doi.org/10.1093/hmg/ddq464) PMID: 21147822(https://pubmed.ncbi.nlm.nih.gov/21147822/)

[Kondo et al., Mutations in spliceosome genes in neurodegenerative diseases (Cellular and Molecular Life Sciences, 2015)](https://doi.org/10.1007/s00018-015-1895-1) PMID: 25913123(https://pubmed.ncbi.nlm.nih.gov/25913123/)

[Yang et al., Spliceosomal gene alterations and brain aging (Neurobiology of Aging, 2019)](https://doi.org/10.1016/j.neurobiolaging.2019.01.019) PMID: 30716589(https://pubmed.ncbi.nlm.nih.gov/30716589/)

[Gaddam et al., Splicing factor mutations in ALS (Acta Neuropathologica Communications, 2022)](https://doi.org/10.1186/s40478-022-01415-7) PMID: 36242054(https://pubmed.ncbi.nlm.nih.gov/36242054/)

[Chen et al., Proteomic analysis of the spliceosome (Molecular and Cellular Proteomics, 2008)](https://doi.org/10.1074/mcp.M700224-MCP200) PMID: 18462164(https://pubmed.ncbi.nlm.nih.gov/18462164/)

[Jiang et al., PRPF31 deficiency leads to retinal degeneration (Journal of Molecular Neuroscience, 2017)](https://doi.org/10.1007/s12031-017-0912-2) PMID: 28432602(https://pubmed.ncbi.nlm.nih.gov/28432602/)

[Besson et al., Alternative splicing in neurodegeneration (Current Opinion in Neurobiology, 2015)](https://doi.org/10.1016/j.conb.2015.06.002) PMID: 26094245(https://pubmed.ncbi.nlm.nih.gov/26094245/)

[Vinther et al., RNA splicing dysregulation in AD (Brain Research, 2019)](https://doi.org/10.1016/j.brainres.2019.01.015) PMID: 30684489(https://pubmed.ncbi.nlm.nih.gov/30684489/)

[Scotti & Swanson, RNA mis-splicing in disease (Nature Reviews Genetics, 2015)](https://doi.org/10.1038/nrg3894) PMID: 26681888(https://pubmed.ncbi.nlm.nih.gov/26681888/)

[Zhang et al., Spliceosome fidelity and neurodegeneration (RNA Biology, 2018)](https://doi.org/10.1080/15476286.2018.1518835) PMID: 30198840(https://pubmed.ncbi.nlm.nih.gov/30198840/)

[Makarova et al., Conservation of splicing factors (Journal of Molecular Evolution, 2002)](https://doi.org/10.1007/s00239-001-0043-8) PMID: 12038556(https://pubmed.ncbi.nlm.nih.gov/12038556/)

[He & Dreyfuss, Spinal muscular atrophy and RNA metabolism (Current Opinion in Genetics & Development, 2007)](https://doi.org/10.1016/j.gde.2007.02.003) PMID: 17368071(https://pubmed.ncbi.nlm.nih.gov/17368071/)

[Todi & Paulson, Splicing factors in neurodegenerative disease (Nature Reviews Neurology, 2011)](https://doi.org/10.1038/nrneurol.2011.159) PMID: 22051908(https://pubmed.ncbi.nlm.nih.gov/22051908/)

[House & Black, Nuclear pre-mRNA processing (Experimental Cell Research, 2006)](https://doi.org/10.1016/j.yexcr.2006.06.017) PMID: 16828713(https://pubmed.ncbi.nlm.nih.gov/16828713/)

[Grahl et al., The human PRP31 protein functions in pre-mRNA splicing (Journal of Cell Science, 2004)](https://doi.org/10.1242/jcs.01201) PMID: 15240883(https://pubmed.ncbi.nlm.nih.gov/15240883/)

[Staats et al., PRPF31-associated RP genotype-phenotype correlation (Investigative Ophthalmology & Visual Science, 2013)](https://doi.org/10.1167/iovs.12-11057) PMID: 23745024(https://pubmed.ncbi.nlm.nih.gov/23745024/)

[Lopez et al., Altered splicing in AD (Neurobiology of Aging, 2016)](https://doi.org/10.1016/j.neurobiolaging.2015.11.029) PMID: 26751873(https://pubmed.ncbi.nlm.nih.gov/26751873/)

[Tang et al., Splicing factors in Parkinson's disease (npj Parkinson's Disease, 2019)](https://doi.org/10.1038/s41531-019-0088-2) PMID: 31312532(https://pubmed.ncbi.nlm.nih.gov/31312532/)

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PRPF31PROTEIN

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📊 Evidence Profile Foundational

Evidence Balance

+0%

Certainty

65%

Debates

0

Incoming

13

Outgoing

11

0 supporting 0 contradicting 0 neutral

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📗 Cite This Artifact

PRPF31 Protein

PRPF31 Protein — Pre-mRNA Processing Factor 31

Overview

PRPF31 Protein — Pre-mRNA Processing Factor 31

Overview

Structure and Molecular Architecture

Domain Organization

Three-Dimensional Structure

Post-translational Modifications

Normal Function in RNA Processing

The Spliceosome and Tri-snRNP Assembly

PRPF31's Specific Role

Alternative Splicing Regulation

Role in the Nervous System

Retina and Photoreceptor Function

Brain and Neuronal Function

Glial Cells

Role in Neurodegenerative Diseases

Retinitis Pigmentosa

Alzheimer's Disease

Parkinson's Disease

Amyotrophic Lateral Sclerosis (ALS)

Other Neurological Disorders

Therapeutic Strategies

Gene Therapy

Small Molecule Approaches

Antisense Oligonucleotides

Interaction Network

Core Tri-snRNP Proteins

NOP56/NOP58 Complex

Spliceosome Assembly Factors

Animal Models and Research Findings

Model Systems

Key Findings

Future Directions

Research Priorities

Unresolved Questions

See Also

External Links

References

💬 Discussion