Biology:PSMB10

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Short description: Protein found in humans


A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example

Proteasome subunit beta type-10 as known as 20S proteasome subunit beta-2i is a protein that in humans is encoded by the PSMB10 gene.[1]

This protein has a major role in the immune system as part of an immunoproteasome that is primarily induced upon infection and formed by replacing constitutive beta subunits with inducible beta subunits which possess specific cleavage properties that aid in the release of peptides necessary for MHC class I antigen presentation.[2] The immunoproteasome appears to have a pivotal role in modulating NFκB signaling.[3]

Structure

Gene

This gene PSMB10 encodes a member of the proteasome B-type family, also known as the T1B family, that is a 20S core beta subunit. Proteolytic processing is required to generate a mature subunit. Expression of this gene is induced by gamma interferon, and this gene product replaces catalytic subunit beta2 (proteasome subunit beta type-7) in the immunoproteasome.[4] The human PSMB10 gene has 8 exons and locates at chromosome band 16q22.1.

Protein structure

The human protein proteasome subunit beta type-8 is 25 kDa in size and composed of 234 amino acids. The calculated theoretical pI of this protein is 6.07.

Complex assembly

Proteasome subunit beta type-10 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-2i, along with other beta subunits, assemble into two heptameric rings and subsequently a proteolytic chamber for substrate degradation. This protein contains "Trypsin-like" activity and is capable of cleaving after basic residues of peptide.[5] The eukaryotic proteasome recognized degradable proteins, including damaged proteins for protein quality control purpose or key regulatory protein components for dynamic biological processes. The constitutive subunit beta1, beta2, and beta 5 (systematic nomenclature) can be replaced by their inducible counterparts beta1i, 2i, and 5i when cells are under the treatment of interferon-γ. The resulting proteasome complex becomes the so-called immunoproteasome. An essential function of the modified proteasome complex, the immunoproteasome, is the processing of numerous MHC class-I restricted T cell epitopes.[6]

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, 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-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.[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]

The 20S proteasome subunit beta-2i (systematic nomenclature) is originally expressed as a precursor with 273 amino acids. The fragment of 39 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 beta2i subunit is cleaved, forming the mature beta2i subunit of 20S complex.[12] During the basal assembly, and proteolytic processing is required to generate a mature subunit. The subunit beta5i only presents in the immunoproteasome and is replaced by subunit beta5(proteasome beta 5 subunit) in constitutive 20S proteasome complex. This protein has an important function in the immune system as part of an immunoproteasome which possess specific cleavage properties that aid in the release of peptides necessary for MHC class I antigen presentation.[2]

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) [13] 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.[14] 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,[15][16] cardiovascular diseases,[17][18][19] inflammatory responses and autoimmune diseases,[20] and systemic DNA damage responses leading to malignancies.[21]

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,[22] Parkinson's disease[23] and Pick's disease,[24] Amyotrophic lateral sclerosis (ALS),[24] Huntington's disease,[23] Creutzfeldt–Jakob disease,[25] and motor neuron diseases, polyglutamine (PolyQ) diseases, Muscular dystrophies[26] and several rare forms of neurodegenerative diseases associated with dementia.[27] As part of the ubiquitin–proteasome system (UPS), the proteasome maintains cardiac protein homeostasis and thus plays a significant role in cardiac ischemic injury,[28] ventricular hypertrophy[29] and heart failure.[30] 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.[31] 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).[20] 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.[32] Lastly, autoimmune disease patients with SLE, Sjögren syndrome and rheumatoid arthritis (RA) predominantly exhibit circulating proteasomes which can be applied as clinical biomarkers.[33]

During the antigen processing for the major histocompatibility complex (MHC) class-I, the proteasome is the major degradation machinery that degrades the antigen and present the resulting peptides to cytotoxic T lymphocytes.[34][35] The immunoproteasome has been considered playing a critical role in improving the quality and quantity of generated class-I ligands.

References

  1. ↑ "A tight cluster of five unrelated human genes on chromosome 16q22.1". Human Molecular Genetics 2 (10): 1589–95. Oct 1993. doi:10.1093/hmg/2.10.1589. PMID 8268911. 
  2. ↑ 2.0 2.1 "Molecular characterization and expressional affirmation of the beta proteasome subunit cluster in rock bream immune defense". Molecular Biology Reports 41 (8): 5413–27. Aug 2014. doi:10.1007/s11033-014-3413-1. PMID 24867079. 
  3. ↑ "Immunoproteasome deficiency modifies the alternative pathway of NFκB signaling". PLOS ONE 8 (2): e56187. 2013. doi:10.1371/journal.pone.0056187. PMID 23457524. Bibcode: 2013PLoSO...856187M. 
  4. ↑ "Entrez Gene: PSMB10 proteasome (prosome, macropain) subunit, beta type, 10". https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=5699. 
  5. ↑ "Structure and functions of the 20S and 26S proteasomes". Annual Review of Biochemistry 65: 801–47. Nov 1996. doi:10.1146/annurev.bi.65.070196.004101. PMID 8811196. 
  6. ↑ "The immunoproteasome in antigen processing and other immunological functions". Current Opinion in Immunology 25 (1): 74–80. Feb 2013. doi:10.1016/j.coi.2012.11.004. PMID 23219269. http://nbn-resolving.de/urn:nbn:de:bsz:352-219861. 
  7. ↑ "Structure and functions of the 20S and 26S proteasomes". Annual Review of Biochemistry 65: 801–47. 1996. doi:10.1146/annurev.bi.65.070196.004101. PMID 8811196. 
  8. ↑ 8.0 8.1 "Molecular architecture and assembly of the eukaryotic proteasome". Annual Review of Biochemistry 82: 415–45. 2013. doi:10.1146/annurev-biochem-060410-150257. PMID 23495936. 
  9. ↑ "Structure of 20S proteasome from yeast at 2.4 A resolution". Nature 386 (6624): 463–71. Apr 1997. doi:10.1038/386463a0. PMID 9087403. Bibcode: 1997Natur.386..463G. 
  10. ↑ 10.0 10.1 "A gated channel into the proteasome core particle". Nature Structural Biology 7 (11): 1062–7. Nov 2000. doi:10.1038/80992. PMID 11062564. 
  11. ↑ "Regulation of murine cardiac 20S proteasomes: role of associating partners". Circulation Research 99 (4): 372–80. Aug 2006. doi:10.1161/01.RES.0000237389.40000.02. PMID 16857963. 
  12. ↑ "In vivo assembly of the proteasomal complexes, implications for antigen processing". The Journal of Biological Chemistry 270 (46): 27687–94. Nov 1995. doi:10.1074/jbc.270.46.27687. PMID 7499235. 
  13. ↑ "Perilous journey: a tour of the ubiquitin–proteasome system". Trends in Cell Biology 24 (6): 352–9. Jun 2014. doi:10.1016/j.tcb.2013.12.003. PMID 24457024. 
  14. ↑ "New insights into proteasome function: from archaebacteria to drug development". Chemistry & Biology 2 (8): 503–8. Aug 1995. doi:10.1016/1074-5521(95)90182-5. PMID 9383453. 
  15. ↑ "The Ubiquitin-Proteasome System and Molecular Chaperone Deregulation in Alzheimer's Disease". Molecular Neurobiology 53 (2): 905–31. Jan 2015. doi:10.1007/s12035-014-9063-4. PMID 25561438. 
  16. ↑ "Ubiquitin-proteasome system involvement in Huntington's disease". Frontiers in Molecular Neuroscience 7: 77. 2014. doi:10.3389/fnmol.2014.00077. PMID 25324717. 
  17. ↑ "Proteotoxicity: an underappreciated pathology in cardiac disease". Journal of Molecular and Cellular Cardiology 71: 3–10. Jun 2014. doi:10.1016/j.yjmcc.2013.12.015. PMID 24380730. 
  18. ↑ "Targeting the ubiquitin-proteasome system in heart disease: the basis for new therapeutic strategies". Antioxidants & Redox Signaling 21 (17): 2322–43. Dec 2014. doi:10.1089/ars.2013.5823. PMID 25133688. 
  19. ↑ "Protein quality control and metabolism: bidirectional control in the heart". Cell Metabolism 21 (2): 215–26. Feb 2015. doi:10.1016/j.cmet.2015.01.016. PMID 25651176. 
  20. ↑ 20.0 20.1 "The I kappa B kinase (IKK) and NF-kappa B: key elements of proinflammatory signalling". Seminars in Immunology 12 (1): 85–98. Feb 2000. doi:10.1006/smim.2000.0210. PMID 10723801. 
  21. ↑ "Quality control mechanisms in cellular and systemic DNA damage responses". Ageing Research Reviews 23 (Pt A): 3–11. Jan 2015. doi:10.1016/j.arr.2014.12.009. PMID 25560147. 
  22. ↑ "Role of the proteasome in Alzheimer's disease". Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease 1502 (1): 133–8. Jul 2000. doi:10.1016/s0925-4439(00)00039-9. PMID 10899438. 
  23. ↑ 23.0 23.1 "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. doi:10.1016/s0166-2236(00)01998-6. PMID 11881748. 
  24. ↑ 24.0 24.1 "Morphometrical reappraisal of motor neuron system of Pick's disease and amyotrophic lateral sclerosis with dementia". Acta Neuropathologica 104 (1): 21–8. Jul 2002. doi:10.1007/s00401-001-0513-5. PMID 12070660. 
  25. ↑ "Marked increase in cerebrospinal fluid ubiquitin in Creutzfeldt–Jakob disease". Neuroscience Letters 139 (1): 47–9. May 1992. doi:10.1016/0304-3940(92)90854-z. PMID 1328965. 
  26. ↑ "Limb-girdle muscular dystrophy". Current Neurology and Neuroscience Reports 3 (1): 78–85. Jan 2003. doi:10.1007/s11910-003-0042-9. PMID 12507416. 
  27. ↑ "From neurodegeneration to neurohomeostasis: the role of ubiquitin". Drug News & Perspectives 16 (2): 103–8. Mar 2003. doi:10.1358/dnp.2003.16.2.829327. PMID 12792671. 
  28. ↑ "The ubiquitin proteasome system and myocardial ischemia". American Journal of Physiology. Heart and Circulatory Physiology 304 (3): H337–49. Feb 2013. doi:10.1152/ajpheart.00604.2012. PMID 23220331. 
  29. ↑ "Ubiquitin proteasome dysfunction in human hypertrophic and dilated cardiomyopathies". Circulation 121 (8): 997–1004. Mar 2010. doi:10.1161/CIRCULATIONAHA.109.904557. PMID 20159828. 
  30. ↑ "The ubiquitin–proteasome system in cardiac physiology and pathology". American Journal of Physiology. Heart and Circulatory Physiology 291 (1): H1–H19. Jul 2006. doi:10.1152/ajpheart.00062.2006. PMID 16501026. 
  31. ↑ "Potential for proteasome inhibition in the treatment of cancer". Drug Discovery Today 8 (7): 307–15. Apr 2003. doi:10.1016/s1359-6446(03)02647-3. PMID 12654543. 
  32. ↑ "Regulatory functions of ubiquitination in the immune system". Nature Immunology 3 (1): 20–6. Jan 2002. doi:10.1038/ni0102-20. PMID 11753406. 
  33. ↑ "Circulating proteasomes are markers of cell damage and immunologic activity in autoimmune diseases". The Journal of Rheumatology 29 (10): 2045–52. Oct 2002. PMID 12375310. 
  34. ↑ "The proteasome inhibitor bortezomib enhances the susceptibility to viral infection". Journal of Immunology 183 (10): 6145–50. Nov 2009. doi:10.4049/jimmunol.0901596. PMID 19841190. 
  35. ↑ "Inhibitors of the proteasome block the degradation of most cell proteins and the generation of peptides presented on MHC class I molecules". Cell 78 (5): 761–71. Sep 1994. doi:10.1016/s0092-8674(94)90462-6. PMID 8087844. 

Further reading




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