PSMD13 Human
Description
Introduction to PSMD13 Human
PSMD13 (Proteasome 26S Subunit, Non-ATPase 13) is a human gene encoding a non-ATPase regulatory subunit of the 19S proteasome complex, a critical component of the ubiquitin-proteasome system (UPS) . Located on chromosome 11, this protein plays a pivotal role in maintaining cellular protein homeostasis by targeting misfolded or damaged proteins for ATP-dependent degradation . PSMD13 is indispensable for processes such as cell cycle regulation, apoptosis, DNA repair, and immune response modulation .
Molecular Structure and Function
The 26S proteasome comprises a 20S core and a 19S regulatory particle. PSMD13 is part of the 19S "lid," which recognizes ubiquitinated substrates and facilitates their deubiquitination and translocation into the proteolytic core .
Key Features:
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Protein Length: 376 amino acids (Human), with a molecular mass of ~45.3 kDa .
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Domains: Contains a PCI (Proteasome, COP9, Initiation factor 3) domain for protein-protein interactions .
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Interactions: Directly interacts with PSMC4 and PSMD6, critical for proteasome assembly .
Functional Roles:
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Mediates degradation of ubiquitinated proteins, ensuring cellular quality control .
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Regulates NF-κB activation, influencing inflammatory and immune responses .
Clinical and Pathological Significance
PSMD13 dysregulation is implicated in multiple diseases due to its central role in protein homeostasis:
Genetic Variants and Disease Associations
Notable SNPs and Their Effects:
Mechanistic Insights:
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rs7128029: Disrupts splicing regulatory elements, leading to exon 2 skipping and truncated protein .
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rs3817629: Reduces proteasome efficiency, accumulating stress-related proteins in neurons .
Research Findings and Therapeutic Implications
Key Studies:
Therapeutic Targets:
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Inhibiting PSMD13 could stabilize mutant RPE65 in retinal diseases .
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Enhancing proteasome activity may alleviate neurodegenerative or psychiatric disorders .
Expression and Recombinant Applications
Tissue Expression:
Recombinant PSMD13 Proteins:
| Product | Source | Purity | Applications | Citation |
|---|---|---|---|---|
| Recombinant Human PSMD13 (E. coli) | Abcam | >90% | SDS-PAGE, functional studies . | |
| HSPC027 (His-tagged) | ProSpec | >95% | Enzyme assays, drug screening . |
Future Directions
Product Specs
Q&A
Basic Research Questions
What is the functional role of PSMD13 in the 26S proteasome complex?
PSMD13 (Proteasome 26S Subunit, Non-ATPase 13) encodes the p40.5 subunit of the 19S regulatory particle, critical for substrate recognition and deubiquitination in the ubiquitin-proteasome system . Methodologically, its role is studied via:
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Knockdown experiments: siRNA-mediated silencing in cell lines to assess proteasomal activity changes (e.g., using fluorogenic substrates like Suc-LLVY-AMC).
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Co-immunoprecipitation: To map interactions with other proteasomal subunits like PSMC1 or PSMD1 .
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Structural studies: Cryo-EM to resolve conformational changes during substrate binding .
How are genetic variants in PSMD13 identified and validated in disease association studies?
Common approaches include:
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Genotyping platforms: Illumina HumanOmniExpress BeadChips for genome-wide SNP analysis (e.g., rs7128029, rs3817629) .
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sQTL analysis: Linking SNPs to alternative splicing events using databases like CancerSplicingQTL and GTEx .
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Functional validation: Spliceman2 or SPANR to predict splicing outcomes (e.g., exon skipping in rs7128029) .
Example Data Table: Key PSMD13 Variants
| SNP ID | Association | p-value | Odds Ratio | Source |
|---|---|---|---|---|
| rs7128029 | Endometrial cancer risk | <0.001 | 1.45 | PMC10157344 |
| rs3817629 | MDD treatment resistance | 0.003 | 1.32 | TP2015180 |
Advanced Research Challenges
How do PSMD13 splicing variants influence cancer progression?
The rs7128029-G allele reduces exon 2 inclusion in PSMD13 transcripts via exon skipping, altering proteasome function . Methodological considerations:
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Spliceosome profiling: CLIP-seq to identify RNA-binding proteins (e.g., hnRNPs) at the variant locus.
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Proteasome activity assays: Compare 20S/26S peptidase activity between splice isoforms using tumor-derived cell lines .
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Survival analysis: Kaplan-Meier plots stratified by splicing ratios (e.g., high vs. low exon 2 inclusion; log-rank p=3.13e-31) .
How can conflicting data on PSMD13’s role in aging and disease be resolved?
PSMD13 and SIRT3 share a bidirectional promoter, creating confounding linkage disequilibrium (LD) in association studies . Strategies include:
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Haplotype analysis: Calculate LD (r²) between PSMD13 (e.g., A21631G) and SIRT3 (e.g., VNTR-intron5) using 1000 Genomes data .
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CRISPR-Cas9 editing: Introduce specific SNPs in iPSC-derived models to isolate PSMD13 effects.
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Multi-omics integration: Merge proteasome activity data with methylation profiles (e.g., TCGA-UCEC cohort) .
What statistical frameworks address pathway-level dysregulation involving PSMD13 in precision oncology?
Patent US20100130527A1 proposes three algorithms for pathway analysis in tumor samples :
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Algorithm 1: Determines pathway significance by counting dysregulated genes (e.g., ≥5 genes with p<0.05).
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Algorithm 2: Aggregates p-values using Fisher’s method (e.g., ) .
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Algorithm 3: Incorporates “privileged elements” (e.g., PSMD13 in proteostasis) with weighted Bayesian probabilities .
Example Table: Algorithm Comparison
| Algorithm | Parameters | Use Case |
|---|---|---|
| 1 | Threshold p-values | Initial hypothesis generation |
| 3 | Weighted priors | Refining subtype-specific pathways |
Methodological Pitfalls
Product Science Overview
The Proteasome 26S Subunit, Non-ATPase 13 (PSMD13), also known as Rpn9 or p40.5, is a crucial component of the 26S proteasome complex in humans. This subunit plays a significant role in the ATP-dependent degradation of ubiquitinated proteins, which is essential for maintaining cellular homeostasis by removing misfolded, damaged, or unnecessary proteins .
The 26S proteasome is a large, multi-protein complex with a molecular mass of approximately 2000 kDa. It consists of a central 20S core proteasome and two 19S regulatory particles attached to either end of the core. The 20S core is composed of four rings of 28 non-identical subunits, while the 19S regulatory particles are divided into a base and a lid. The base contains six ATPase subunits and two non-ATPase subunits, and the lid contains up to ten non-ATPase subunits, including PSMD13 .
PSMD13 is involved in the regulation of the proteasome’s activity. The 26S proteasome plays a key role in various cellular processes, including:
- Protein Homeostasis: By degrading misfolded or damaged proteins, the proteasome prevents the accumulation of potentially toxic proteins that could impair cellular functions .
- Cell Cycle Progression: The proteasome regulates the levels of cyclins and other cell cycle-related proteins, ensuring proper cell cycle progression .
- Apoptosis: The degradation of pro-apoptotic and anti-apoptotic proteins by the proteasome influences the cell’s decision to undergo programmed cell death .
- DNA Damage Repair: The proteasome is involved in the degradation of proteins that participate in the DNA damage response, thereby facilitating the repair process .
Dysfunction or alterations in the proteasome system, including PSMD13, have been implicated in various diseases, such as cancer, neurodegenerative disorders, and autoimmune diseases. The proteasome’s role in degrading misfolded proteins is particularly relevant in neurodegenerative diseases like Alzheimer’s and Parkinson’s, where the accumulation of misfolded proteins is a hallmark .
Given its central role in protein degradation, the proteasome, and by extension PSMD13, is a target for therapeutic interventions. Proteasome inhibitors, such as bortezomib, are already used in the treatment of multiple myeloma and other cancers. Ongoing research aims to develop more specific inhibitors that can target particular subunits of the proteasome, potentially leading to more effective and less toxic treatments .
