| 词条 | PSMB1 |
| 释义 |
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.[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-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. StructureGeneThe 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.[2] The gene has 6 exons and locates at chromosome band 6q27. ProteinThe 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 assemblyThe 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] FunctionProtein 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.[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 significanceThe 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) [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),[4] Huntington's disease,[18] Creutzfeldt–Jakob disease,[20] and motor neuron diseases, polyglutamine (PolyQ) diseases, Muscular dystrophies[21] and several rare forms of neurodegenerative diseases associated with dementia.[22] As part of the Ubiquitin-Proteasome System (UPS), the proteasome maintains cardiac protein homeostasis and thus plays a significant role in cardiac Ischemic injury,[23] ventricular hypertrophy[24] and Heart failure.[25] 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.[26] 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.[27] Lastly, autoimmune disease patients with SLE, Sjogren's syndrome and rheumatoid arthritis (RA) predominantly exhibit circulating proteasomes which can be applied as clinical biomarkers.[28]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.[29] Overall, the PSMB1 protein has been described in several forms of malignancies[30][31][32] such as follicular lymphoma[31] with an important mechanistic role in tumorigenesis.[33] References1. ^{{cite journal | vauthors = Tamura T, Lee DH, Osaka F, Fujiwara T, Shin S, Chung CH, Tanaka K, Ichihara A | title = Molecular cloning and sequence analysis of cDNAs for five major subunits of human proteasomes (multi-catalytic proteinase complexes) | journal = Biochimica et Biophysica Acta | volume = 1089 | issue = 1 | pages = 95–102 | date = May 1991 | pmid = 2025653 | pmc = | doi = 10.1016/0167-4781(91)90090-9 }} 2. ^{{cite web | title = Entrez Gene: PSMB1 proteasome (prosome, macropain) subunit, beta type, 1| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=5689| accessdate = }} 3. ^{{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 | pages = 801–47 | date = 1996 | pmid = 8811196 | doi = 10.1146/annurev.bi.65.070196.004101 }} 4. ^1 2 {{cite journal | vauthors = Tomko RJ, Hochstrasser M | title = Molecular architecture and assembly of the eukaryotic proteasome | journal = Annual Review of Biochemistry | volume = 82 | pages = 415–45 | date = 2013 | pmid = 23495936 | pmc = 3827779 | doi = 10.1146/annurev-biochem-060410-150257 }} 5. ^{{cite journal | vauthors = Groll M, Ditzel L, Löwe J, Stock D, Bochtler M, Bartunik HD, Huber R | title = Structure of 20S proteasome from yeast at 2.4 A resolution | journal = Nature | volume = 386 | issue = 6624 | pages = 463–71 | date = Apr 1997 | pmid = 9087403 | doi = 10.1038/386463a0 | bibcode = 1997Natur.386..463G }} 6. ^1 {{cite journal | vauthors = Groll M, Bajorek M, Köhler A, Moroder L, Rubin 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Heart and Circulatory Physiology | volume = 291 | issue = 1 | pages = H1–H19 | date = Jul 2006 | pmid = 16501026 | doi = 10.1152/ajpheart.00062.2006 }} 26. ^{{cite journal | vauthors = Adams J | title = Potential for proteasome inhibition in the treatment of cancer | journal = Drug Discovery Today | volume = 8 | issue = 7 | pages = 307–15 | date = Apr 2003 | pmid = 12654543 | doi=10.1016/s1359-6446(03)02647-3}} 27. ^{{cite journal | vauthors = Ben-Neriah Y | title = Regulatory functions of ubiquitination in the immune system | journal = Nature Immunology | volume = 3 | issue = 1 | pages = 20–6 | date = Jan 2002 | pmid = 11753406 | doi = 10.1038/ni0102-20 }} 28. ^{{cite journal | vauthors = Egerer K, Kuckelkorn U, Rudolph PE, Rückert JC, Dörner T, Burmester GR, Kloetzel PM, Feist E | title = Circulating proteasomes are markers of cell damage and immunologic activity in autoimmune diseases | journal = The Journal of Rheumatology | volume = 29 | issue = 10 | pages = 2045–52 | date = Oct 2002 | pmid = 12375310 }} 29. ^{{cite journal | vauthors = Yamauchi J, Sekiguchi M, Shirai T, Yamada M, Ishimi Y | title = Role of nuclear localization of PSMB1 in transcriptional activation | journal = Bioscience, Biotechnology, and Biochemistry | volume = 77 | issue = 8 | pages = 1785–7 | date = 2013 | pmid = 23924720 | doi = 10.1271/bbb.130290 }} 30. ^{{cite journal | vauthors = Singh V, Sharma V, Verma V, Pandey D, Yadav SK, Maikhuri JP, Gupta G | title = Apigenin manipulates the ubiquitin-proteasome system to rescue estrogen receptor-β from degradation and induce apoptosis in prostate cancer cells | journal = European Journal of Nutrition | date = Nov 2014 | pmid = 25408199 | doi = 10.1007/s00394-014-0803-z | volume=54 | issue = 8 | pages=1255–67}} 31. ^1 {{cite journal | vauthors = Barton MK | title = Predictive biomarkers may help individualize treatment for patients with follicular lymphoma | journal = CA: A Cancer Journal for Clinicians | volume = 63 | issue = 5 | pages = 293–4 | date = Sep 2013 | pmid = 23842891 | doi = 10.3322/caac.21197 }} 32. ^{{cite journal | vauthors = Feng L, Zhang D, Fan C, Ma C, Yang W, Meng Y, Wu W, Guan S, Jiang B, Yang M, Liu X, Guo D | title = ER stress-mediated apoptosis induced by celastrol in cancer cells and important role of glycogen synthase kinase-3β in the signal network | journal = Cell Death & Disease | volume = 4 | issue = 7 | pages = e715 | date = 11 July 2013 | pmid = 23846217 | pmc = 3730400 | doi = 10.1038/cddis.2013.222 }} 33. ^{{cite journal | vauthors = Yuan F, Ma Y, You P, Lin W, Lu H, Yu Y, Wang X, Jiang J, Yang P, Ma Q, Tao T | title = A novel role of proteasomal β1 subunit in tumorigenesis | journal = Bioscience Reports | volume = 33 | issue = 4 | pages = 555–565 | date = 16 July 2013 | pmid = 23725357 | pmc = 3712487 | doi = 10.1042/BSR20130013 }} Further reading{{refbegin|33em}}
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