PSMB1
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 4R3O, 4R67, 5A0Q
Identifiers
Aliases	PSMB1, HC5, PMSB1, PSC5, proteasome subunit beta 1, proteasome 20S subunit beta 1
External IDs	OMIM: 602017; MGI: 104884; HomoloGene: 2087; GeneCards: PSMB1; OMA: PSMB1 - orthologs
Gene location ( Human) Chr. Chromosome 6 (human) [1] Band 6q27 Start 170,535,120 bp [1] End 170,553,307 bp [1]
Gene location ( Mouse) Chr. Chromosome 17 (mouse) [2] Band 17 A2|17 8.95 cM Start 15,695,283 bp [2] End 15,720,013 bp [2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in gingival epithelium parietal pleura visceral pleura epithelium of nasopharynx retinal pigment epithelium amniotic fluid middle temporal gyrus tibia seminal vesicula germinal epithelium Top expressed in medial ganglionic eminence facial motor nucleus transitional epithelium of urinary bladder efferent ductule anterior horn of spinal cord endocardial cushion abdominal wall right lung lobe otic placode maxillary prominence More reference expression data BioGPS More reference expression data
Gene ontology Molecular function endopeptidase activity peptidase activity protein binding threonine-type endopeptidase activity hydrolase activity Cellular component cytoplasm cytosol nucleoplasm proteasome complex extracellular exosome nucleus proteasome core complex extracellular region secretory granule lumen ficolin-1-rich granule lumen proteasome core complex, beta-subunit complex Biological process regulation of cellular amino acid metabolic process antigen processing and presentation of exogenous peptide antigen via MHC class I, TAP-dependent regulation of mRNA stability positive regulation of canonical Wnt signaling pathway protein polyubiquitination stimulatory C-type lectin receptor signaling pathway tumor necrosis factor-mediated signaling pathway MAPK cascade proteolysis Fc-epsilon receptor signaling pathway NIK/NF-kappaB signaling anaphase-promoting complex-dependent catabolic process proteolysis involved in cellular protein catabolic process T cell receptor signaling pathway negative regulation of canonical Wnt signaling pathway proteasome-mediated ubiquitin-dependent protein catabolic process viral process Wnt signaling pathway, planar cell polarity pathway negative regulation of G2/M transition of mitotic cell cycle protein deubiquitination SCF-dependent proteasomal ubiquitin-dependent protein catabolic process neutrophil degranulation transmembrane transport regulation of transcription from RNA polymerase II promoter in response to hypoxia post-translational protein modification regulation of hematopoietic stem cell differentiation proteasomal protein catabolic process proteasomal ubiquitin-independent protein catabolic process interleukin-1-mediated signaling pathway regulation of mitotic cell cycle phase transition Sources: Amigo / QuickGO
Orthologs Species Human Mouse Entrez 5689 19170 Ensembl ENSG00000008018 ENSG00000281184 ENSMUSG00000014769 UniProt P20618 O09061 RefSeq (mRNA) NM_002793 NM_011185 RefSeq (protein) NP_002784 NP_035315 Location (UCSC) Chr 6: 170.54 – 170.55 Mb Chr 17: 15.7 – 15.72 Mb PubMed search [3] [4]
Wikidata
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Proteasome subunit beta type-1 also known as 20S proteasome subunit beta-6 (based on systematic nomenclature) is a protein that in humans is encoded by the PSMB1 gene. ^[5] This protein is one of the 17 essential subunits (alpha subunits 1-7, constitutive beta subunits 1-7, and inducible subunits including beta1i, beta2i, beta5i) that contributes to the complete assembly of 20S proteasome complex. In particular, proteasome subunit beta type-1, along with other beta subunits, assemble into two heptameric rings and subsequently a proteolytic chamber for substrate degradation. The eukaryotic proteasome recognized degradable proteins, including damaged proteins for protein quality control purpose or key regulatory protein components for dynamic biological processes. An essential function of a modified proteasome, the immunoproteasome, is the processing of class I MHC peptides.

Structure

Gene

The gene PSMB1 encodes a member of the proteasome B-type family, also known as the T1B family, that is a 20S core beta subunit. This gene is tightly linked to the TBP (TATA-binding protein) gene in human and in mouse, and is transcribed in the opposite orientation in both species. ^[6] The gene has 6 exons and locates at chromosome band 6q27.

Protein

The human protein proteasome subunit beta type-1 is 26.5 kDa in size and composed of 241 amino acids. The calculated theoretical pI of this protein is 8.27.

Complex assembly

The proteasome is a multicatalytic proteinase complex with a highly ordered 20S core structure. This barrel-shaped core structure is composed of 4 axially stacked rings of 28 non-identical subunits: the two end rings are each formed by 7 alpha subunits, and the two central rings are each formed by 7 beta subunits. Three beta subunits (beta1, beta2, and beta5) each contains a proteolytic active site and has distinct substrate preferences. Proteasomes are distributed throughout eukaryotic cells at a high concentration and cleave peptides in an ATP/ubiquitin-dependent process in a non-lysosomal pathway. ^{[7] [8]}

Function

Protein functions are supported by its tertiary structure and its interaction with associating partners. As one of 28 subunits of 20S proteasome, protein proteasome subunit beta type-1 contributes to form a proteolytic environment for substrate degradation. Evidences of the crystal structures of isolated 20S proteasome complex demonstrate that the two rings of beta subunits form a proteolytic chamber and maintain all their active sites of proteolysis within the chamber. ^[8] Concomitantly, the rings of alpha subunits form the entrance for substrates entering the proteolytic chamber. In an inactivated 20S proteasome complex, the gate into the internal proteolytic chamber are guarded by the N-terminal tails of specific alpha-subunit. This unique structure design prevents random encounter between proteolytic active sites and protein substrate, which makes protein degradation a well-regulated process. ^{[9] [10]} 20S proteasome complex, by itself, is usually functionally inactive. The proteolytic capacity of 20S core particle (CP) can be activated when CP associates with one or two regulatory particles (RP) on one or both side of alpha rings. These regulatory particles include 19S proteasome complexes, 11S proteasome complex, etc. Following the CP-RP association, the confirmation of certain alpha subunits will change and consequently cause the opening of substrate entrance gate. Besides RPs, the 20S proteasomes can also be effectively activated by other mild chemical treatments, such as exposure to low levels of sodium dodecylsulfate (SDS) or NP-14. ^{[10] [11]}

Clinical significance

The proteasome and its subunits are of clinical significance for at least two reasons: (1) a compromised complex assembly or a dysfunctional proteasome can be associated with the underlying pathophysiology of specific diseases, and (2) they can be exploited as drug targets for therapeutic interventions. More recently, more effort has been made to consider the proteasome for the development of novel diagnostic markers and strategies. An improved and comprehensive understanding of the pathophysiology of the proteasome should lead to clinical applications in the future.

The proteasomes form a pivotal component for the ubiquitin–proteasome system (UPS) ^[12] and corresponding cellular Protein Quality Control (PQC). Protein ubiquitination and subsequent proteolysis and degradation by the proteasome are important mechanisms in the regulation of the cell cycle, cell growth and differentiation, gene transcription, signal transduction and apoptosis. ^[13] Subsequently, a compromised proteasome complex assembly and function lead to reduced proteolytic activities and the accumulation of damaged or misfolded protein species. Such protein accumulation may contribute to the pathogenesis and phenotypic characteristics in neurodegenerative diseases, ^{[14] [15]} cardiovascular diseases, ^{[16] [17] [18]} inflammatory responses and autoimmune diseases, ^[19] and systemic DNA damage responses leading to malignancies. ^[20]

Several experimental and clinical studies have indicated that aberrations and deregulations of the UPS contribute to the pathogenesis of several neurodegenerative and myodegenerative disorders, including Alzheimer's disease, ^[21] Parkinson's disease ^[22] and Pick's disease, ^[23] Amyotrophic lateral sclerosis (ALS), ^[8] Huntington's disease, ^[22] Creutzfeldt–Jakob disease, ^[24] and motor neuron diseases, polyglutamine (PolyQ) diseases, Muscular dystrophies ^[25] and several rare forms of neurodegenerative diseases associated with dementia. ^[26] As part of the ubiquitin–proteasome system (UPS), the proteasome maintains cardiac protein homeostasis and thus plays a significant role in cardiac ischemic injury, ^[27] ventricular hypertrophy ^[28] and heart failure. ^[29] Additionally, evidence is accumulating that the UPS plays an essential role in malignant transformation. UPS proteolysis plays a major role in responses of cancer cells to stimulatory signals that are critical for the development of cancer. Accordingly, gene expression by degradation of transcription factors, such as p53, c-jun, c-Fos, NF-κB, c-Myc, HIF-1α, MATα2, STAT3, sterol-regulated element-binding proteins and androgen receptors are all controlled by the UPS and thus involved in the development of various malignancies. ^[30] Moreover, the UPS regulates the degradation of tumor suppressor gene products such as adenomatous polyposis coli (APC) in colorectal cancer, retinoblastoma (Rb). and von Hippel–Lindau tumor suppressor (VHL), as well as a number of proto-oncogenes ( Raf, Myc, Myb, Rel, Src, Mos, ABL). The UPS is also involved in the regulation of inflammatory responses. This activity is usually attributed to the role of proteasomes in the activation of NF-κB which further regulates the expression of pro inflammatory cytokines such as TNF-α, IL-β, IL-8, adhesion molecules ( ICAM-1, VCAM-1, P-selectin) and prostaglandins and nitric oxide (NO). ^[19] Additionally, the UPS also plays a role in inflammatory responses as regulators of leukocyte proliferation, mainly through proteolysis of cyclines and the degradation of CDK inhibitors. ^[31] Lastly, autoimmune disease patients with SLE, Sjögren syndrome and rheumatoid arthritis (RA) predominantly exhibit circulating proteasomes which can be applied as clinical biomarkers. ^[32]

The proteasome subunit beta type-1 (also known as 20S proteasome subunit beta-6) is a protein encoded by the PSMB1 gene in humans and has been a subject of investigations in several clinical conditions. For instance, a mutated form of PSMB1 displayed an increased nuclear translocation, which resulted in the activation of transcription in adipocytes relevant in diabetes mellitus. ^[33] Overall, the PSMB1 protein has been described in several forms of malignancies ^{[34] [35] [36]} such as follicular lymphoma ^[35] with an important mechanistic role in tumorigenesis. ^[37]

References

Further reading