PSMB5
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 4R3O, 4R67, 5A0Q
Identifiers
Aliases	PSMB5, LMPX, MB1, proteasome subunit beta 5, X, proteasome 20S subunit beta 5
External IDs	OMIM: 600306 MGI: 1194513 HomoloGene: 55690 GeneCards: PSMB5
Gene location (Human) Chr. Chromosome 14 (human)[1] Band 14q11.2 Start 23,016,543 bp[1] End 23,035,230 bp[1]
Gene location (Mouse) Chr. Chromosome 14 (mouse)[2] Band 14 C2|14 27.86 cM Start 54,851,576 bp[2] End 54,855,479 bp[2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in gastrocnemius muscle islet of Langerhans stromal cell of endometrium right adrenal gland ganglionic eminence left adrenal gland deltoid muscle smooth muscle tissue prefrontal cortex tibialis anterior muscle Top expressed in proximal tubule lens neural tube adrenal gland quadriceps femoris muscle lip mesencephalon foregut stomach ganglionic eminence 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 centrosome nucleoplasm proteasome complex extracellular exosome nucleus proteasome core complex 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 response to oxidative stress proteolysis MAPK cascade 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 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 5693 19173 Ensembl ENSG00000100804 ENSMUSG00000022193 UniProt P28074 O55234 RefSeq (mRNA) NM_001130725 NM_001144932 NM_002797 NM_011186 RefSeq (protein) NP_001124197 NP_001138404 NP_002788 NP_035316 Location (UCSC) Chr 14: 23.02 – 23.04 Mb Chr 14: 54.85 – 54.86 Mb PubMed search [3] [4]
Wikidata
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Proteasome subunit beta type-5 as known as 20S proteasome subunit beta-5 is a protein that in humans is encoded by the PSMB5 gene.^[5][6][7] 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-5, along with other beta subunits, assemble into two heptameric rings and subsequently a proteolytic chamber for substrate degradation. This protein contains "chymotrypsin-like" activity and is capable of cleaving after large hydrophobic residues of peptide.^[6] 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

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-2 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.^[9] 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.^[10][11] 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.^[11][12]

The 20S proteasome subunit beta-5 (systematic nomenclature) is originally expressed as a precursor with 263 amino acids. The fragment of 59 amino acids at peptide N-terminal is essential for proper protein folding and subsequent complex assembly. At the end-stage of complex assembly, the N-terminal fragment of beta5 subunit is cleaved, forming the mature beta5 subunit of 20S complex.^[13]

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) ^[14] 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.^[15] 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,^[16][17] cardiovascular diseases,^[18][19][20] inflammatory responses and autoimmune diseases,^[21] and systemic DNA damage responses leading to malignancies.^[22]

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,^[23] Parkinson's disease^[24] and Pick's disease,^[25] Amyotrophic lateral sclerosis (ALS),^[25] Huntington's disease,^[24] Creutzfeldt–Jakob disease,^[26] and motor neuron diseases, polyglutamine (PolyQ) diseases, Muscular dystrophies^[27] and several rare forms of neurodegenerative diseases associated with dementia.^[28] As part of the ubiquitin–proteasome system (UPS), the proteasome maintains cardiac protein homeostasis and thus plays a significant role in cardiac ischemic injury,^[29] ventricular hypertrophy^[30] and heart failure.^[31] 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.^[32] 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).^[33] 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.^[34] Lastly, autoimmune disease patients with SLE, Sjögren syndrome and rheumatoid arthritis (RA) predominantly exhibit circulating proteasomes which can be applied as clinical biomarkers.^[35]

Radiation therapy is a critical modality in the treatment of cancer. Accordingly, the proteasome subunit alpha type-1 was examined as a strategy in radio sensitizing for the treatment of non-small cell lung carcinomas. Proteasome inhibition through the knockdown of PSMA1 resulting in loss of protein expression of the proteasome subunit alpha type-1 and the proteasome chymotrypsin-like activity and also in a loss of expression of PSMB5 protein (proteasome subunit beta type-5). A combination of PSMA1 knockdown in parallel with radiation therapy to treat non-small cell lung carcinoma resulted in an increased sensitivity of the tumor to radiation and improved tumor control.^[36] The study suggests that proteasome inhibition through PSMA1 knockdown is a promising strategy for non-small cell lung carcinomas radiosensitization via inhibition of NF-κB-mediated expression of Fanconi anemia/HR DNA repair genes, and that the proteasome subunit beta type-5 may play a significant role in this process.^[36]

References

Further reading