1. Structure
     Gene    Protein    Complex assembly  

2. Function

3. Clinical significance

4. References

5. Further reading

Proteasome subunit beta type-2 also known as 20S proteasome subunit beta-4 (based on systematic nomenclature) is a protein that in humans is encoded by the PSMB2 gene.^[1] 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-2, 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 PSMB2 encodes a member of the proteasome B-type family, also known as the T1B family, that is a 20S core beta subunit.^[2] The gene has 7 exons and locates at chromosome band 1p34.2.

Protein

The human protein proteasome subunit beta type-2 is 23 kDa in size and composed of 201 amino acids. The calculated theoretical pI of this protein is 6.52.

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.^[3][4]

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.^[4] 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.^[5][6] 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.^[6][7]

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. 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) ^[8] 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.^[9] 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,^[10][11] cardiovascular diseases,^[12][13][14] inflammatory responses and autoimmune diseases,^[15] and systemic DNA damage responses leading to malignancies.^[16]

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,^[17] Parkinson's disease^[18] and Pick's disease,^[19] Amyotrophic lateral sclerosis (ALS),^[19] Huntington's disease, Creutzfeldt–Jakob disease, and motor neuron diseases, polyglutamine (PolyQ) diseases, Muscular dystrophies^[20] and several rare forms of neurodegenerative diseases associated with dementia.^[21] As part of the Ubiquitin-Proteasome System (UPS), the proteasome maintains cardiac protein homeostasis and thus plays a significant role in cardiac Ischemic injury,^[22] ventricular hypertrophy^[23] and Heart failure.^[24] 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.^[25] 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).^[15] 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.^[26] Lastly, autoimmune disease patients with SLE, Sjogren's syndrome and rheumatoid arthritis (RA) predominantly exhibit circulating proteasomes which can be applied as clinical biomarkers.^[27]

The proteasome subunit beta type-2 also known as 20S proteasome subunit beta-4, a protein encoded by the PSMB2 gene in humans has shown to be stable in broncho alveolar cells (BAL) of the lung during certain clinical conditions such as interstitial lung disease and sarcoidosis (in parallel with RPL32). PSMB2 is therefore, a suitable reference gene for normalization in BAL cells in sarcoidosis, and other interstitial lung disease during clinical studies applying quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR.^[28]

References

Further reading

• {{cite journal | vauthors = Coux O, Tanaka K, Goldberg AL | title = Structure and functions of the 20S and 26S proteasomes | journal = Annual Review of Biochemistry | volume = 65 | issue = | pages = 801–47 | year = 1996 | pmid = 8811196 | doi = 10.1146/annurev.bi.65.070196.004101 }}
• {{cite journal | vauthors = Goff SP | title = Death by deamination: a novel host restriction system for HIV-1 | journal = Cell | volume = 114 | issue = 3 | pages = 281–3 | date = Aug 2003 | pmid = 12914693 | doi = 10.1016/S0092-8674(03)00602-0 }}
• {{cite journal | vauthors = Rasmussen HH, van Damme J, Puype M, Gesser B, Celis JE, Vandekerckhove J | title = Microsequences of 145 proteins recorded in the two-dimensional gel protein database of normal human epidermal keratinocytes | journal = Electrophoresis | volume = 13 | issue = 12 | pages = 960–9 | date = Dec 1992 | pmid = 1286667 | doi = 10.1002/elps.11501301199 }}
• {{cite journal | vauthors = Dawson SJ, White LA | title = Treatment of Haemophilus aphrophilus endocarditis with ciprofloxacin | journal = The Journal of Infection | volume = 24 | issue = 3 | pages = 317–20 | date = May 1992 | pmid = 1602151 | doi = 10.1016/S0163-4453(05)80037-4 }}
• {{cite journal | vauthors = Kristensen P, Johnsen AH, Uerkvitz W, Tanaka K, Hendil KB | title = Human proteasome subunits from 2-dimensional gels identified by partial sequencing | journal = Biochemical and Biophysical Research Communications | volume = 205 | issue = 3 | pages = 1785–9 | date = Dec 1994 | pmid = 7811265 | doi = 10.1006/bbrc.1994.2876 }}
• {{cite journal | vauthors = Seeger M, Ferrell K, Frank R, Dubiel W | title = HIV-1 tat inhibits the 20 S proteasome and its 11 S regulator-mediated activation | journal = The Journal of Biological Chemistry | volume = 272 | issue = 13 | pages = 8145–8 | date = Mar 1997 | pmid = 9079628 | doi = 10.1074/jbc.272.13.8145 }}
• {{cite journal | vauthors = McCusker D, Jones T, Sheer D, Trowsdale J | title = Genetic relationships of the genes encoding the human proteasome beta subunits and the proteasome PA28 complex | journal = Genomics | volume = 45 | issue = 2 | pages = 362–7 | date = Oct 1997 | pmid = 9344661 | doi = 10.1006/geno.1997.4948 }}
• {{cite journal | vauthors = Madani N, Kabat D | title = An endogenous inhibitor of human immunodeficiency virus in human lymphocytes is overcome by the viral Vif protein | journal = Journal of Virology | volume = 72 | issue = 12 | pages = 10251–5 | date = Dec 1998 | pmid = 9811770 | pmc = 110608 | doi = }}
• {{cite journal | vauthors = Simon JH, Gaddis NC, Fouchier RA, Malim MH | title = Evidence for a newly discovered cellular anti-HIV-1 phenotype | journal = Nature Medicine | volume = 4 | issue = 12 | pages = 1397–400 | date = Dec 1998 | pmid = 9846577 | doi = 10.1038/3987 }}
• {{cite journal | vauthors = Elenich LA, Nandi D, Kent AE, McCluskey TS, Cruz M, Iyer MN, Woodward EC, Conn CW, Ochoa AL, Ginsburg DB, Monaco JJ | title = The complete primary structure of mouse 20S proteasomes | journal = Immunogenetics | volume = 49 | issue = 10 | pages = 835–42 | date = Sep 1999 | pmid = 10436176 | doi = 10.1007/s002510050562 }}
• {{cite journal | vauthors = Mulder LC, Muesing MA | title = Degradation of HIV-1 integrase by the N-end rule pathway | journal = The Journal of Biological Chemistry | volume = 275 | issue = 38 | pages = 29749–53 | date = Sep 2000 | pmid = 10893419 | doi = 10.1074/jbc.M004670200 }}
• {{cite journal | vauthors = Feng Y, Longo DL, Ferris DK | title = Polo-like kinase interacts with proteasomes and regulates their activity | journal = Cell Growth & Differentiation | volume = 12 | issue = 1 | pages = 29–37 | date = Jan 2001 | pmid = 11205743 | doi = }}
• {{cite journal | vauthors = Sheehy AM, Gaddis NC, Choi JD, Malim MH | title = Isolation of a human gene that inhibits HIV-1 infection and is suppressed by the viral Vif protein | journal = Nature | volume = 418 | issue = 6898 | pages = 646–50 | date = Aug 2002 | pmid = 12167863 | doi = 10.1038/nature00939 | bibcode = 2002Natur.418..646S }}
• {{cite journal | vauthors = Huang X, Seifert U, Salzmann U, Henklein P, Preissner R, Henke W, Sijts AJ, Kloetzel PM, Dubiel W | title = The RTP site shared by the HIV-1 Tat protein and the 11S regulator subunit alpha is crucial for their effects on proteasome function including antigen processing | journal = Journal of Molecular Biology | volume = 323 | issue = 4 | pages = 771–82 | date = Nov 2002 | pmid = 12419264 | doi = 10.1016/S0022-2836(02)00998-1 }}
• {{cite journal | vauthors = De M, Jayarapu K, Elenich L, Monaco JJ, Colbert RA, Griffin TA | title = Beta 2 subunit propeptides influence cooperative proteasome assembly | journal = The Journal of Biological Chemistry | volume = 278 | issue = 8 | pages = 6153–9 | date = Feb 2003 | pmid = 12456675 | doi = 10.1074/jbc.M209292200 }}
• {{cite journal | vauthors = Gaddis NC, Chertova E, Sheehy AM, Henderson LE, Malim MH | title = Comprehensive investigation of the molecular defect in vif-deficient human immunodeficiency virus type 1 virions | journal = Journal of Virology | volume = 77 | issue = 10 | pages = 5810–20 | date = May 2003 | pmid = 12719574 | pmc = 154025 | doi = 10.1128/JVI.77.10.5810-5820.2003 }}
• {{cite journal | vauthors = Lecossier D, Bouchonnet F, Clavel F, Hance AJ | title = Hypermutation of HIV-1 DNA in the absence of the Vif protein | journal = Science | volume = 300 | issue = 5622 | pages = 1112 | date = May 2003 | pmid = 12750511 | doi = 10.1126/science.1083338 }}

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