PSMA6

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Proteasome (prosome, macropain) subunit, alpha type, 6
Protein PSMA6 PDB 1iru.png
PDB rendering based on 1iru.
Available structures
PDB Ortholog search: PDBe, RCSB
Identifiers
Symbols PSMA6 ; IOTA; PROS27; p27K
External IDs OMIM602855 MGI1347006 HomoloGene2085 GeneCards: PSMA6 Gene
EC number 3.4.25.1
RNA expression pattern
PBB GE PSMA6 208805 at tn.png
More reference expression data
Orthologs
Species Human Mouse
Entrez 5687 26443
Ensembl ENSG00000100902 ENSMUSG00000021024
UniProt P60900 Q9QUM9
RefSeq (mRNA) NM_001282232 NM_011968
RefSeq (protein) NP_001269161 NP_036098
Location (UCSC) Chr 14:
35.59 – 35.79 Mb
Chr 12:
55.38 – 55.42 Mb
PubMed search [1] [2]

Proteasome subunit alpha type-6 is a protein that in humans is encoded by the PSMA6 gene.[1][2][3] 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.

Structure[edit]

Protein Expression[edit]

The gene PMSA6 encodes a member of the peptidase T1A family, that is a 20S core alpha subunit. A pseudogene has been identified on the Y chromosome.[3] The gene has 8 exons and locates at chromosome band 14q13. The human protein Proteasome subunit alpha type-6 is also known as 20S proteasome subunit alpha-1 (based on systematic nomenclature). The protein is 27 kDa in size and composed of 246 amino acids. The calculated theoretical pI (isoelectric point) of this protein is 6.35.

Complex Assembly[edit]

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.[4][5]

Function[edit]

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.[6][7] 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] As a component of alpha ring, Proteasome subunit alpha type-6 contributes to the formation of heptameric alpha rings and substrate entrance gate.

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.

Clinical significance[edit]

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) [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,[5] Amyotrophic lateral sclerosis (ALS),[5] Huntington's disease,[19] Creutzfeldt-Jacob 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 selectine) and prostaglandins and nitric oxide (NO).[27] 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.[28] Lastly, autoimmune disease patients with SLE, Sjogren's syndrome and rheumatoid arthritis (RA) predominantly exhibit circulating proteasomes which can be applied as clinical biomarkers.[29]

PSMA6 has been implicated to be involved in the pathogenesis of ankylosing spondylitis (AS) and may therefore be a potential biomarker in this autoimmune disease.[30] The same study exploring AS also suggested that RPL17, MRPL22, PSMA4 in addition to PSMA6 are involved in the pathogenesis of AS and may be potential biomarkers for clinical application as well.[31]

Interactions[edit]

PSMA6 has been shown to interact with PLK1[32] and PSMA3.[33][34]

References[edit]

  1. ^ DeMartino GN, Orth K, McCullough ML, Lee LW, Munn TZ, Moomaw CR et al. (Oct 1991). "The primary structures of four subunits of the human, high-molecular-weight proteinase, macropain (proteasome), are distinct but homologous". Biochim Biophys Acta 1079 (1): 29–38. doi:10.1016/0167-4838(91)90020-Z. PMID 1888762. 
  2. ^ Coux O, Tanaka K, Goldberg AL (Nov 1996). "Structure and functions of the 20S and 26S proteasomes". Annu Rev Biochem 65: 801–47. doi:10.1146/annurev.bi.65.070196.004101. PMID 8811196. 
  3. ^ a b "Entrez Gene: PSMA6 proteasome (prosome, macropain) subunit, alpha type, 6". 
  4. ^ Coux O, Tanaka K, Goldberg AL (1996). "Structure and functions of the 20S and 26S proteasomes". Annual Review of Biochemistry 65: 801–47. doi:10.1146/annurev.bi.65.070196.004101. PMID 8811196. 
  5. ^ a b c d Tomko RJ, Hochstrasser M (2013). "Molecular architecture and assembly of the eukaryotic proteasome". Annual Review of Biochemistry 82: 415–45. doi:10.1146/annurev-biochem-060410-150257. PMID 23495936. 
  6. ^ Groll M, Ditzel L, Löwe J, Stock D, Bochtler M, Bartunik HD et al. (Apr 1997). "Structure of 20S proteasome from yeast at 2.4 A resolution". Nature 386 (6624): 463–71. doi:10.1038/386463a0. PMID 9087403. 
  7. ^ a b Groll M, Bajorek M, Köhler A, Moroder L, Rubin DM, Huber R et al. (Nov 2000). "A gated channel into the proteasome core particle". Nature Structural Biology 7 (11): 1062–7. doi:10.1038/80992. PMID 11062564. 
  8. ^ Zong, C; Gomes, AV; Drews, O; Li, X; Young, GW; Berhane, B; Qiao, X; French, SW; Bardag-Gorce, F; Ping, P (18 August 2006). "Regulation of murine cardiac 20S proteasomes: role of associating partners.". Circulation research 99 (4): 372–80. PMID 16857963. 
  9. ^ Kleiger G, Mayor T (Jun 2014). "Perilous journey: a tour of the ubiquitin-proteasome system". Trends in Cell Biology 24 (6): 352–9. doi:10.1016/j.tcb.2013.12.003. PMID 24457024. 
  10. ^ Goldberg, AL; Stein, R; Adams, J (August 1995). "New insights into proteasome function: from archaebacteria to drug development.". Chemistry & biology 2 (8): 503–8. PMID 9383453. 
  11. ^ Sulistio YA, Heese K (Jan 2015). "The Ubiquitin-Proteasome System and Molecular Chaperone Deregulation in Alzheimer's Disease". Molecular Neurobiology. doi:10.1007/s12035-014-9063-4. PMID 25561438. 
  12. ^ Ortega Z, Lucas JJ (2014). "Ubiquitin-proteasome system involvement in Huntington's disease". Frontiers in Molecular Neuroscience 7: 77. doi:10.3389/fnmol.2014.00077. PMID 25324717. 
  13. ^ Sandri M, Robbins J (Jun 2014). "Proteotoxicity: an underappreciated pathology in cardiac disease". Journal of Molecular and Cellular Cardiology 71: 3–10. doi:10.1016/j.yjmcc.2013.12.015. PMID 24380730. 
  14. ^ Drews O, Taegtmeyer H (Dec 2014). "Targeting the ubiquitin-proteasome system in heart disease: the basis for new therapeutic strategies". Antioxidants & Redox Signaling 21 (17): 2322–43. doi:10.1089/ars.2013.5823. PMID 25133688. 
  15. ^ Wang ZV, Hill JA (Feb 2015). "Protein quality control and metabolism: bidirectional control in the heart". Cell Metabolism 21 (2): 215–26. doi:10.1016/j.cmet.2015.01.016. PMID 25651176. 
  16. ^ . PMID 10723801.  Missing or empty |title= (help)
  17. ^ Ermolaeva MA, Dakhovnik A, Schumacher B (Jan 2015). "Quality control mechanisms in cellular and systemic DNA damage responses". Ageing Research Reviews. doi:10.1016/j.arr.2014.12.009. PMID 25560147. 
  18. ^ Checler, F; da Costa, CA; Ancolio, K; Chevallier, N; Lopez-Perez, E; Marambaud, P (26 July 2000). "Role of the proteasome in Alzheimer's disease.". Biochimica et biophysica acta 1502 (1): 133–8. PMID 10899438. 
  19. ^ a b Chung, KK; Dawson, VL; Dawson, TM (November 2001). "The role of the ubiquitin-proteasomal pathway in Parkinson's disease and other neurodegenerative disorders.". Trends in neurosciences 24 (11 Suppl): S7–14. PMID 11881748. 
  20. ^ Manaka, H; Kato, T; Kurita, K; Katagiri, T; Shikama, Y; Kujirai, K; Kawanami, T; Suzuki, Y; Nihei, K; Sasaki, H (11 May 1992). "Marked increase in cerebrospinal fluid ubiquitin in Creutzfeldt-Jakob disease.". Neuroscience letters 139 (1): 47–9. PMID 1328965. 
  21. ^ Mathews, KD; Moore, SA (January 2003). "Limb-girdle muscular dystrophy.". Current neurology and neuroscience reports 3 (1): 78–85. PMID 12507416. 
  22. ^ Mayer, RJ (March 2003). "From neurodegeneration to neurohomeostasis: the role of ubiquitin.". Drug news & perspectives 16 (2): 103–8. PMID 12792671. 
  23. ^ . PMID 23220331.  Missing or empty |title= (help)
  24. ^ Predmore, JM; Wang, P; Davis, F; Bartolone, S; Westfall, MV; Dyke, DB; Pagani, F; Powell, SR; Day, SM (2 March 2010). "Ubiquitin proteasome dysfunction in human hypertrophic and dilated cardiomyopathies.". Circulation 121 (8): 997–1004. PMID 20159828. 
  25. ^ Powell, SR (July 2006). "The ubiquitin-proteasome system in cardiac physiology and pathology.". American journal of physiology. Heart and circulatory physiology 291 (1): H1–H19. PMID 16501026. 
  26. ^ Adams, J (1 April 2003). "Potential for proteasome inhibition in the treatment of cancer.". Drug discovery today 8 (7): 307–15. PMID 12654543. 
  27. ^ Karin, M; Delhase, M (February 2000). "The I kappa B kinase (IKK) and NF-kappa B: key elements of proinflammatory signalling.". Seminars in immunology 12 (1): 85–98. PMID 10723801. 
  28. ^ Ben-Neriah, Y (January 2002). "Regulatory functions of ubiquitination in the immune system.". Nature immunology 3 (1): 20–6. PMID 11753406. 
  29. ^ Egerer, K; Kuckelkorn, U; Rudolph, PE; Rückert, JC; Dörner, T; Burmester, GR; Kloetzel, PM; Feist, E (October 2002). "Circulating proteasomes are markers of cell damage and immunologic activity in autoimmune diseases.". The Journal of rheumatology 29 (10): 2045–52. PMID 12375310. 
  30. ^ Zhao, H; Wang, D; Fu, D; Xue, L (29 November 2014). "Predicting the potential ankylosing spondylitis-related genes utilizing bioinformatics approaches.". Rheumatology international. PMID 25432079. 
  31. ^ Zhao, H; Wang, D; Fu, D; Xue, L (29 November 2014). "Predicting the potential ankylosing spondylitis-related genes utilizing bioinformatics approaches.". Rheumatology international. PMID 25432079. 
  32. ^ Feng Y, Longo DL, Ferris DK (Jan 2001). "Polo-like kinase interacts with proteasomes and regulates their activity". Cell Growth Differ. 12 (1): 29–37. PMID 11205743. 
  33. ^ Stelzl U, Worm U, Lalowski M, Haenig C, Brembeck FH, Goehler H et al. (Sep 2005). "A human protein-protein interaction network: a resource for annotating the proteome". Cell 122 (6): 957–68. doi:10.1016/j.cell.2005.08.029. PMID 16169070. 
  34. ^ Gerards WL, de Jong WW, Bloemendal H, Boelens W (Jan 1998). "The human proteasomal subunit HsC8 induces ring formation of other alpha-type subunits". J. Mol. Biol. 275 (1): 113–21. doi:10.1006/jmbi.1997.1429. PMID 9451443. 

Further reading[edit]