# PSMB1

## Overview
The PSMB1 gene encodes the proteasome 20S subunit beta 1, a critical component of the proteasome complex involved in protein degradation. This subunit, also known as β6, is integral to the function of the 20S proteasome, which, in combination with the 19S regulatory particles, forms the 26S proteasome complex responsible for degrading ubiquitinated proteins. The proteasome plays a vital role in maintaining cellular protein homeostasis and regulating various cellular processes, including the cell cycle, inflammation, and differentiation. The PSMB1 protein is characterized by its chymotrypsin-like activity, which is essential for the proteasome's function in protein turnover and cellular regulation. Mutations in PSMB1 have been linked to neurodevelopmental disorders and certain cancers, highlighting its significance in both normal cellular function and disease (Jiang2022Comprehensive; Ansar2020Biallelic).

## Structure
The PSMB1 gene encodes a subunit of the 20S proteasome, specifically the β6 subunit, which is integral to the proteasome's function in protein degradation. The primary structure of the PSMB1 protein consists of 241 amino acids, with a predicted molecular weight of 26.36 kDa and an isoelectric point of 7.1 (Wang2017Proteasome). The protein includes several functional sites, such as phosphorylation sites, N-myristoylation sites, and a prenyl group binding site (CAAX box) (Wang2017Proteasome).

The secondary structure of PSMB1 includes a proteasome domain spanning amino acids 34 to 226, which contains a PHD domain (residues 70-106) and a T-BOX domain (residues 115-219) (Wang2017Proteasome). The tertiary structure of PSMB1 has been modeled to provide insights into the spatial arrangement of these domains, covering residues 29-241 (Wang2017Proteasome).

In terms of quaternary structure, PSMB1 is part of the 20S proteasome complex, interacting with other subunits such as PSMA5. A specific mutation, p.(Tyr103His), affects the interaction between PSMB1 and PSMA5, destabilizing the 20S proteasome complex (Ansar2020Biallelic). This mutation disrupts a hydrogen bond and a T-type π stacking interaction, potentially impacting the stability of the proteasome (Ansar2020Biallelic).

## Function
The PSMB1 gene encodes the proteasome subunit β6, a critical component of the 20S proteasome complex, which plays a vital role in protein degradation and maintaining cellular protein homeostasis. The 20S proteasome, in conjunction with 19S regulatory particles, forms the 26S proteasome complex, which is responsible for degrading ubiquitinated proteins. This process is essential for regulating various cellular pathways, including those involved in inflammation, differentiation, and proliferation (Ansar2020Biallelic).

In healthy human cells, PSMB1 is crucial for the proper assembly and function of the proteasome. It facilitates the degradation of proteins through its chymotrypsin-like activity, which is necessary for maintaining protein homeostasis and regulating the cell cycle (Ansar2020Biallelic). The PSMB1 subunit is involved in interactions with other proteasome subunits, such as PSMA5, and these interactions are important for the stability of the proteasome complex (Ansar2020Biallelic).

The proteasome's activity is not only vital for protein turnover but also for ensuring proper cellular function, as it removes misfolded or damaged proteins. This activity is crucial for normal cellular processes and organismal development, as evidenced by the severe phenotypes associated with PSMB1 dysfunction (Ansar2020Biallelic).

## Clinical Significance
Mutations in the PSMB1 gene, which encodes the proteasome subunit β6, are associated with several neurodevelopmental disorders. Notably, biallelic variants in PSMB1 can lead to a condition characterized by microcephaly, intellectual disability, developmental delay, and short stature. A specific mutation, p.(Tyr103His), has been identified as causing impaired proteasome function by destabilizing the 20S proteasome complex, which affects its chymotrypsin-like activity (Ansar2020Biallelic). This mutation results in decreased incorporation of PSMB1 into proteasomes, leading to reduced proteasome activity (Ansar2020Biallelic).

In contrast to other proteasome-related conditions like CANDLE/PRAAS, which involve systemic inflammation, PSMB1 mutations primarily result in neurodevelopmental disorders without inflammatory symptoms. This suggests a unique impact of PSMB1 mutations on central nervous system development (Ansar2020Biallelic; Poli2023Proteasome).

Alterations in PSMB1 expression have also been linked to cancer. In clear cell renal cell carcinoma (ccRCC), PSMB1 is highly expressed, correlating with a higher malignant degree and worse prognosis, indicating its potential oncogenic role (Jiang2022Comprehensive).

## Interactions
PSMB1, a component of the 20S core proteasome complex, participates in several critical protein interactions. It interacts with PSMA5, another subunit of the 20S proteasome complex. The interaction involves the Tyr103 residue of PSMB1 forming a hydrogen bond with Glu105 in PSMA5 and a T-type π stacking interaction with Tyr103 in PSMA5. The p.(Tyr103His) mutation in PSMB1 disrupts these interactions, potentially destabilizing the 20S proteasome complex and impairing its function (Ansar2020Biallelic).

PSMB1 also interacts with Rheb, a small GTPase involved in the mTORC1 pathway, in Cashmere goat fetal fibroblasts. This interaction was confirmed through yeast two-hybrid screening and co-immunoprecipitation assays. The interaction between PSMB1 and Rheb is significant for cell cycle regulation, as silencing PSMB1 leads to cell cycle arrest, while overexpression of Rheb increases the number of S phase cells and enhances growth efficiency (Wang2017Proteasome).

Additionally, PSMB1 is involved in transcriptional activation in adipocytes, where it acts as a transcriptional activator of the Rbp4 promoter. Its nuclear localization and transcriptional activity are influenced by phosphorylation at tyrosine 149 (YAMAUCHI2013Role).


## References


[1. (Poli2023Proteasome) M. Cecilia Poli. Proteasome disorders and inborn errors of immunity. Immunological Reviews, 322(1):283–299, December 2023. URL: http://dx.doi.org/10.1111/imr.13299, doi:10.1111/imr.13299. This article has 2 citations and is from a domain leading peer-reviewed journal.](https://doi.org/10.1111/imr.13299)

[2. (Wang2017Proteasome) Yanfeng Wang, Zhixin Guo, Mingtao Liu, Keyu Zhao, Xue Feng, Xu Zheng, Xiaojing Wang, Huifang Hao, Xudong Guo, and Zhigang Wang. Proteasome subunit beta type 1 interacts directly with rheb and regulates the cell cycle in cashmere goat fetal fibroblasts. Animal Cells and Systems, 21(5):307–315, September 2017. URL: http://dx.doi.org/10.1080/19768354.2017.1371072, doi:10.1080/19768354.2017.1371072. This article has 2 citations and is from a peer-reviewed journal.](https://doi.org/10.1080/19768354.2017.1371072)

[3. (Ansar2020Biallelic) Muhammad Ansar, Frédéric Ebstein, Hayriye Özkoç, Sohail A Paracha, Justyna Iwaszkiewicz, Matthias Gesemann, Vincent Zoete, Emmanuelle Ranza, Federico A Santoni, Muhammad T Sarwar, Jawad Ahmed, Elke Krüger, Ruxandra Bachmann-Gagescu, and Stylianos E Antonarakis. Biallelic variants in psmb1 encoding the proteasome subunit β6 cause impairment of proteasome function, microcephaly, intellectual disability, developmental delay and short stature. Human Molecular Genetics, 29(7):1132–1143, March 2020. URL: http://dx.doi.org/10.1093/hmg/ddaa032, doi:10.1093/hmg/ddaa032. This article has 42 citations and is from a domain leading peer-reviewed journal.](https://doi.org/10.1093/hmg/ddaa032)

4. (Jiang2022Comprehensive) Comprehensive Analysis of the Expression and Prognosis for PSMBs in Clear Cell Renal Cell Carcinoma. This article has 0 citations.

[5. (YAMAUCHI2013Role) Jun YAMAUCHI, Mariko SEKIGUCHI, Tomomi SHIRAI, Mami YAMADA, and Yoshiko ISHIMI. Role of nuclear localization of psmb1 in transcriptional activation. Bioscience, Biotechnology, and Biochemistry, 77(8):1785–1787, August 2013. URL: http://dx.doi.org/10.1271/bbb.130290, doi:10.1271/bbb.130290. This article has 6 citations.](https://doi.org/10.1271/bbb.130290)