PSMB3 explained

Proteasome subunit beta type-3, also known as 20S proteasome subunit beta-3, is a protein that in humans is encoded by the PSMB3 gene.[1] This protein is one of the 17 essential subunits[2] that contribute to the complete assembly of the 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 recognizes degradable proteins, including damaged proteins for protein quality control purpose or key regulatory protein components for dynamic biological processes.

Structure

Protein expression

The gene PSMB3 encodes a member of the proteasome B-type family, also known as the T1B family, that is a 20S core beta subunit. Pseudogenes have been identified on chromosomes 2 and 12.[3] The gene has 6 exons and locates at chromosome band 17q12. The human protein proteasome subunit beta type-3 is 23 kDa in size and composed of 205 amino acids. The calculated theoretical pI of this protein is 6.14.

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 contain a proteolytic active site and have 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.[4] [5]

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-3 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.[5] 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.[6] [7] 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.[7] [8]

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) [9] 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.[10] 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,[11] [12] cardiovascular diseases,[13] [14] [15] inflammatory responses and autoimmune diseases,[16] and systemic DNA damage responses leading to malignancies.[17]

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,[18] Parkinson's disease[19] and Pick's disease,[20] Amyotrophic lateral sclerosis (ALS),[20] Huntington's disease, Creutzfeldt–Jakob disease, 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).[16] 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, Sjögren syndrome and rheumatoid arthritis (RA) predominantly exhibit circulating proteasomes which can be applied as clinical biomarkers.[28]

Interactions

PSMB3 has been shown to interact with PLK1.[29]

Further reading

Notes and References

  1. Nothwang HG, Tamura T, Tanaka K, Ichihara A . Sequence analyses and inter-species comparisons of three novel human proteasomal subunits, HsN3, HsC7-I and HsC10-II, confine potential proteolytic active-site residues . Biochimica et Biophysica Acta (BBA) - Gene Structure and Expression . 1219 . 2 . 361–8 . Oct 1994 . 7918633 . 10.1016/0167-4781(94)90060-4 .
  2. Alongside alpha subunits 1-7, constitutive beta subunits 1-7, and inducible subunits including beta1i, beta2i, beta5i
  3. Web site: Entrez Gene: PSMB3 proteasome (prosome, macropain) subunit, beta type, 3.
  4. Coux O, Tanaka K, Goldberg AL . Structure and functions of the 20S and 26S proteasomes . Annual Review of Biochemistry . 65 . 801–47 . 1996 . 8811196 . 10.1146/annurev.bi.65.070196.004101 .
  5. Tomko RJ, Hochstrasser M . Molecular architecture and assembly of the eukaryotic proteasome . Annual Review of Biochemistry . 82 . 415–45 . 2013 . 23495936 . 3827779 . 10.1146/annurev-biochem-060410-150257 .
  6. Groll M, Ditzel L, Löwe J, Stock D, Bochtler M, Bartunik HD, Huber R . Structure of 20S proteasome from yeast at 2.4 A resolution . Nature . 386 . 6624 . 463–71 . Apr 1997 . 9087403 . 10.1038/386463a0 . 1997Natur.386..463G . 4261663 .
  7. Groll M, Bajorek M, Köhler A, Moroder L, Rubin DM, Huber R, Glickman MH, Finley D . A gated channel into the proteasome core particle . Nature Structural Biology . 7 . 11 . 1062–7 . Nov 2000 . 11062564 . 10.1038/80992 . 27481109 .
  8. Zong C, Gomes AV, Drews O, Li X, Young GW, Berhane B, Qiao X, French SW, Bardag-Gorce F, Ping P . Regulation of murine cardiac 20S proteasomes: role of associating partners . Circulation Research . 99 . 4 . 372–80 . Aug 2006 . 16857963 . 10.1161/01.RES.0000237389.40000.02 . free .
  9. Kleiger G, Mayor T . Perilous journey: a tour of the ubiquitin–proteasome system . Trends in Cell Biology . 24 . 6 . 352–9 . Jun 2014 . 24457024 . 4037451 . 10.1016/j.tcb.2013.12.003 .
  10. Goldberg AL, Stein R, Adams J . New insights into proteasome function: from archaebacteria to drug development . Chemistry & Biology . 2 . 8 . 503–8 . Aug 1995 . 9383453 . 10.1016/1074-5521(95)90182-5 . free .
  11. Sulistio YA, Heese K . The Ubiquitin–Proteasome System and Molecular Chaperone Deregulation in Alzheimer's Disease . Molecular Neurobiology . Jan 2015 . 25561438 . 10.1007/s12035-014-9063-4 . 53 . 2 . 905–31. 14103185 .
  12. Ortega Z, Lucas JJ . Ubiquitin–proteasome system involvement in Huntington's disease . Frontiers in Molecular Neuroscience . 7 . 77 . 2014 . 25324717 . 4179678 . 10.3389/fnmol.2014.00077 . free .
  13. Sandri M, Robbins J . Proteotoxicity: an underappreciated pathology in cardiac disease . Journal of Molecular and Cellular Cardiology . 71 . 3–10 . Jun 2014 . 24380730 . 4011959 . 10.1016/j.yjmcc.2013.12.015 .
  14. Drews O, Taegtmeyer H . Targeting the ubiquitin-proteasome system in heart disease: the basis for new therapeutic strategies . Antioxidants & Redox Signaling . 21 . 17 . 2322–43 . Dec 2014 . 25133688 . 4241867 . 10.1089/ars.2013.5823 .
  15. Wang ZV, Hill JA . Protein quality control and metabolism: bidirectional control in the heart . Cell Metabolism . 21 . 2 . 215–26 . Feb 2015 . 25651176 . 4317573 . 10.1016/j.cmet.2015.01.016 .
  16. Karin M, Delhase M . The I kappa B kinase (IKK) and NF-kappa B: key elements of proinflammatory signalling . Seminars in Immunology . 12 . 1 . 85–98 . Feb 2000 . 10723801 . 10.1006/smim.2000.0210 .
  17. Ermolaeva MA, Dakhovnik A, Schumacher B . Quality control mechanisms in cellular and systemic DNA damage responses . Ageing Research Reviews . 23 . Pt A . 3–11 . Sep 2015 . 25560147 . 10.1016/j.arr.2014.12.009 . 4886828.
  18. Checler F, da Costa CA, Ancolio K, Chevallier N, Lopez-Perez E, Marambaud P . Role of the proteasome in Alzheimer's disease . Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease . 1502 . 1 . 133–8 . Jul 2000 . 10899438 . 10.1016/s0925-4439(00)00039-9 .
  19. Chung KK, Dawson VL, Dawson TM . The role of the ubiquitin-proteasomal pathway in Parkinson's disease and other neurodegenerative disorders . Trends in Neurosciences . 24 . 11 Suppl . S7–14 . Nov 2001 . 11881748 . 10.1016/s0166-2236(00)01998-6. 2211658 .
  20. Ikeda K, Akiyama H, Arai T, Ueno H, Tsuchiya K, Kosaka K . Morphometrical reappraisal of motor neuron system of Pick's disease and amyotrophic lateral sclerosis with dementia . Acta Neuropathologica . 104 . 1 . 21–8 . Jul 2002 . 12070660 . 10.1007/s00401-001-0513-5 . 22396490 .
  21. Mathews KD, Moore SA . Limb-girdle muscular dystrophy . Current Neurology and Neuroscience Reports . 3 . 1 . 78–85 . Jan 2003 . 12507416 . 10.1007/s11910-003-0042-9 . 5780576 .
  22. Mayer RJ . From neurodegeneration to neurohomeostasis: the role of ubiquitin . Drug News & Perspectives . 16 . 2 . 103–8 . Mar 2003 . 12792671 . 10.1358/dnp.2003.16.2.829327 .
  23. Calise J, Powell SR . The ubiquitin proteasome system and myocardial ischemia . American Journal of Physiology. Heart and Circulatory Physiology . 304 . 3 . H337–49 . Feb 2013 . 23220331 . 3774499 . 10.1152/ajpheart.00604.2012 .
  24. Predmore JM, Wang P, Davis F, Bartolone S, Westfall MV, Dyke DB, Pagani F, Powell SR, Day SM . Ubiquitin proteasome dysfunction in human hypertrophic and dilated cardiomyopathies . Circulation . 121 . 8 . 997–1004 . Mar 2010 . 20159828 . 10.1161/circulationaha.109.904557 . 2857348.
  25. Powell SR . The ubiquitin–proteasome system in cardiac physiology and pathology . American Journal of Physiology. Heart and Circulatory Physiology . 291 . 1 . H1–H19 . Jul 2006 . 16501026 . 10.1152/ajpheart.00062.2006 . 7073263 .
  26. Adams J . Potential for proteasome inhibition in the treatment of cancer . Drug Discovery Today . 8 . 7 . 307–15 . Apr 2003 . 12654543 . 10.1016/s1359-6446(03)02647-3 .
  27. Ben-Neriah Y . Regulatory functions of ubiquitination in the immune system . Nature Immunology . 3 . 1 . 20–6 . Jan 2002 . 11753406 . 10.1038/ni0102-20 . 26973319 .
  28. Egerer K, Kuckelkorn U, Rudolph PE, Rückert JC, Dörner T, Burmester GR, Kloetzel PM, Feist E . Circulating proteasomes are markers of cell damage and immunologic activity in autoimmune diseases . The Journal of Rheumatology . 29 . 10 . 2045–52 . Oct 2002 . 12375310 .
  29. Feng Y, Longo DL, Ferris DK . Polo-like kinase interacts with proteasomes and regulates their activity . Cell Growth & Differentiation . 12 . 1 . 29–37 . Jan 2001 . 11205743 .

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