PSMA6

Proteasome subunit alpha type-6 is a protein that in humans is encoded by the PSMA6 gene.[4][5][6] 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.

PSMA6
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 4R3O, 4R67, 1IRU, 5A0Q
Identifiers
Aliases	PSMA6, IOTA, PROS27, p27K, proteasome subunit alpha 6, proteasome 20S subunit alpha 6
External IDs	OMIM: 602855 MGI: 1347006 HomoloGene: 2085 GeneCards: PSMA6
Gene location (Mouse) Chr. Chromosome 12 (mouse)[1] Band 12|12 C1 Start 55,384,222 bp[1] End 55,418,454 bp[1]
RNA expression pattern More reference expression data
Gene ontology Molecular function • endopeptidase activity • NF-kappaB binding • purine ribonucleoside triphosphate binding • peptidase activity • GO:0001948 protein binding • RNA binding • threonine-type endopeptidase activity • hydrolase activity Cellular component • polysome • nuclear matrix • P-body • proteasome complex • extracellular exosome • cell nucleus • proteasome core complex • nucleoplasm • cytoplasm • cytosol • proteasome core complex, alpha-subunit complex • myofibril • sarcomere Biological process • regulation of cellular amino acid metabolic process • antigen processing and presentation of exogenous peptide antigen via MHC class I, TAP-dependent • ubiquitin-dependent protein catabolic process • regulation of mRNA stability • positive regulation of canonical Wnt signaling pathway • protein polyubiquitination • stimulatory C-type lectin receptor signaling pathway • tumor necrosis factor-mediated signaling pathway • proteolysis • MAPK cascade • Fc-epsilon receptor signaling pathway • NIK/NF-kappaB signaling • positive regulation of NF-kappaB transcription factor activity • regulation of inflammatory response • anaphase-promoting complex-dependent catabolic process • proteolysis involved in cellular protein catabolic process • T cell receptor signaling pathway • negative regulation of canonical Wnt signaling pathway • proteasome-mediated ubiquitin-dependent protein catabolic process • Wnt signaling pathway, planar cell polarity pathway • negative regulation of G2/M transition of mitotic cell cycle • protein deubiquitination • SCF-dependent proteasomal ubiquitin-dependent protein catabolic process • transmembrane transport • regulation of transcription from RNA polymerase II promoter in response to hypoxia • post-translational modification • regulation of hematopoietic stem cell differentiation • proteasomal protein catabolic process • proteasomal ubiquitin-independent protein catabolic process • interleukin-1-mediated signaling pathway • regulation of mitotic cell cycle phase transition Sources:Amigo / QuickGO
Orthologs
Species	Human	Mouse
Entrez	5687	26443
Ensembl	ENSG00000100902	ENSMUSG00000021024
UniProt	P60900	Q9QUM9
RefSeq (mRNA)	NM_001282232 NM_001282233 NM_001282234 NM_002791	NM_011968 NM_001310583
RefSeq (protein)	NP_001269161 NP_001269162 NP_001269163 NP_002782	NP_001297512 NP_036098
Location (UCSC)	n/a	Chr 12: 55.38 – 55.42 Mb
PubMed search	[2]	[3]
Wikidata
View/Edit Human View/Edit Mouse

Structure

Protein expression

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.[6] 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

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.[7][8]

Function

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.[9][10] 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] 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

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) [12] 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.[13] 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,[14][15] cardiovascular diseases,[16][17][18] inflammatory responses and autoimmune diseases,[19] and systemic DNA damage responses leading to malignancies.[20]

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,[21] Parkinson's disease[22] and Pick's disease,[23] Amyotrophic lateral sclerosis (ALS),[23] Huntington's disease,[22] Creutzfeldt–Jakob disease,[24] and motor neuron diseases, polyglutamine (PolyQ) diseases, Muscular dystrophies[25] and several rare forms of neurodegenerative diseases associated with dementia.[26] As part of the ubiquitin–proteasome system (UPS), the proteasome maintains cardiac protein homeostasis and thus plays a significant role in cardiac ischemic injury,[27] ventricular hypertrophy[28] and heart failure.[29] 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.[30] 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).[19] 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.[31] Lastly, autoimmune disease patients with SLE, Sjögren syndrome and rheumatoid arthritis (RA) predominantly exhibit circulating proteasomes which can be applied as clinical biomarkers.[32]

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.[33] 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.[33]

Interactions

PSMA6 has been shown to interact with PLK1[34] and PSMA3.[35][36]

References

1. GRCm38: Ensembl release 89: ENSMUSG00000021024 - Ensembl, May 2017
2. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
3. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
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5. Coux O, Tanaka K, Goldberg AL (Nov 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.
6. "Entrez Gene: PSMA6 proteasome (prosome, macropain) subunit, alpha type, 6".
7. 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.
8. 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. PMC 3827779. PMID 23495936.
9. Groll M, Ditzel L, Löwe J, Stock D, Bochtler M, Bartunik HD, Huber R (April 1997). "Structure of 20S proteasome from yeast at 2.4 A resolution". Nature. 386 (6624): 463–71. Bibcode:1997Natur.386..463G. doi:10.1038/386463a0. PMID 9087403.
10. Groll M, Bajorek M, Köhler A, Moroder L, Rubin DM, Huber R, Glickman MH, Finley D (November 2000). "A gated channel into the proteasome core particle". Nature Structural Biology. 7 (11): 1062–7. doi:10.1038/80992. PMID 11062564.
11. Zong C, Gomes AV, Drews O, Li X, Young GW, Berhane B, Qiao X, French SW, Bardag-Gorce F, Ping P (August 2006). "Regulation of murine cardiac 20S proteasomes: role of associating partners". Circulation Research. 99 (4): 372–80. doi:10.1161/01.res.0000237389.40000.02. PMID 16857963.
12. Kleiger G, Mayor T (June 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. PMC 4037451. PMID 24457024.
13. Goldberg AL, Stein R, Adams J (August 1995). "New insights into proteasome function: from archaebacteria to drug development". Chemistry & Biology. 2 (8): 503–8. doi:10.1016/1074-5521(95)90182-5. PMID 9383453.
14. Sulistio YA, Heese K (March 2016). "The Ubiquitin–Proteasome System and Molecular Chaperone Deregulation in Alzheimer's Disease". Molecular Neurobiology. 53 (2): 905–31. doi:10.1007/s12035-014-9063-4. PMID 25561438.
15. 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. PMC 4179678. PMID 25324717.
16. Sandri M, Robbins J (June 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. PMC 4011959. PMID 24380730.
17. Drews O, Taegtmeyer H (December 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. PMC 4241867. PMID 25133688.
18. Wang ZV, Hill JA (February 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. PMC 4317573. PMID 25651176.
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21. Checler F, da Costa CA, Ancolio K, Chevallier N, Lopez-Perez E, Marambaud P (July 2000). "Role of the proteasome in Alzheimer's disease". Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease. 1502 (1): 133–8. doi:10.1016/s0925-4439(00)00039-9. PMID 10899438.
22. 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. doi:10.1016/s0166-2236(00)01998-6. PMID 11881748.
23. Ikeda K, Akiyama H, Arai T, Ueno H, Tsuchiya K, Kosaka K (July 2002). "Morphometrical reappraisal of motor neuron system of Pick's disease and amyotrophic lateral sclerosis with dementia". Acta Neuropathologica. 104 (1): 21–8. doi:10.1007/s00401-001-0513-5. PMID 12070660.
24. Manaka H, Kato T, Kurita K, Katagiri T, Shikama Y, Kujirai K, Kawanami T, Suzuki Y, Nihei K, Sasaki H (May 1992). "Marked increase in cerebrospinal fluid ubiquitin in Creutzfeldt-Jakob disease". Neuroscience Letters. 139 (1): 47–9. doi:10.1016/0304-3940(92)90854-z. PMID 1328965.
25. Mathews KD, Moore SA (January 2003). "Limb-girdle muscular dystrophy". Current Neurology and Neuroscience Reports. 3 (1): 78–85. doi:10.1007/s11910-003-0042-9. PMID 12507416.
26. Mayer RJ (March 2003). "From neurodegeneration to neurohomeostasis: the role of ubiquitin". Drug News & Perspectives. 16 (2): 103–8. doi:10.1358/dnp.2003.16.2.829327. PMID 12792671.
27. Calise J, Powell SR (February 2013). "The ubiquitin proteasome system and myocardial ischemia". American Journal of Physiology. Heart and Circulatory Physiology. 304 (3): H337–49. doi:10.1152/ajpheart.00604.2012. PMC 3774499. PMID 23220331.
28. Predmore JM, Wang P, Davis F, Bartolone S, Westfall MV, Dyke DB, Pagani F, Powell SR, Day SM (March 2010). "Ubiquitin proteasome dysfunction in human hypertrophic and dilated cardiomyopathies". Circulation. 121 (8): 997–1004. doi:10.1161/circulationaha.109.904557. PMC 2857348. PMID 20159828.
29. 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. doi:10.1152/ajpheart.00062.2006. PMID 16501026.
30. Adams J (April 2003). "Potential for proteasome inhibition in the treatment of cancer". Drug Discovery Today. 8 (7): 307–15. doi:10.1016/s1359-6446(03)02647-3. PMID 12654543.
31. Ben-Neriah Y (January 2002). "Regulatory functions of ubiquitination in the immune system". Nature Immunology. 3 (1): 20–6. doi:10.1038/ni0102-20. PMID 11753406.
32. 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.
33. Zhao H, Wang D, Fu D, Xue L (June 2015). "Predicting the potential ankylosing spondylitis-related genes utilizing bioinformatics approaches". Rheumatology International. 35 (6): 973–9. doi:10.1007/s00296-014-3178-9. PMID 25432079.
34. Feng Y, Longo DL, Ferris DK (January 2001). "Polo-like kinase interacts with proteasomes and regulates their activity". Cell Growth & Differentiation. 12 (1): 29–37. PMID 11205743.
35. Stelzl U, Worm U, Lalowski M, Haenig C, Brembeck FH, Goehler H, Stroedicke M, Zenkner M, Schoenherr A, Koeppen S, Timm J, Mintzlaff S, Abraham C, Bock N, Kietzmann S, Goedde A, Toksöz E, Droege A, Krobitsch S, Korn B, Birchmeier W, Lehrach H, Wanker EE (September 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. hdl:11858/00-001M-0000-0010-8592-0. PMID 16169070.
36. Gerards WL, de Jong WW, Bloemendal H, Boelens W (January 1998). "The human proteasomal subunit HsC8 induces ring formation of other alpha-type subunits". Journal of Molecular Biology. 275 (1): 113–21. doi:10.1006/jmbi.1997.1429. PMID 9451443.

Further reading

• Goff SP (August 2003). "Death by deamination: a novel host restriction system for HIV-1". Cell. 114 (3): 281–3. doi:10.1016/S0092-8674(03)00602-0. PMID 12914693.
• Bey F, Silva Pereira I, Coux O, Viegas-Péquignot E, Recillas Targa F, Nothwang HG, Dutrillaux B, Scherrer K (February 1993). "The prosomal RNA-binding protein p27K is a member of the alpha-type human prosomal gene family". Molecular & General Genetics. 237 (1–2): 193–205. doi:10.1007/BF00282801. PMID 7681138.
• Kristensen P, Johnsen AH, Uerkvitz W, Tanaka K, Hendil KB (December 1994). "Human proteasome subunits from 2-dimensional gels identified by partial sequencing". Biochemical and Biophysical Research Communications. 205 (3): 1785–9. doi:10.1006/bbrc.1994.2876. PMID 7811265.
• Kato S, Sekine S, Oh SW, Kim NS, Umezawa Y, Abe N, Yokoyama-Kobayashi M, Aoki T (December 1994). "Construction of a human full-length cDNA bank". Gene. 150 (2): 243–50. doi:10.1016/0378-1119(94)90433-2. PMID 7821789.
• Nederlof PM, Wang HR, Baumeister W (December 1995). "Nuclear localization signals of human and Thermoplasma proteasomal alpha subunits are functional in vitro". Proceedings of the National Academy of Sciences of the United States of America. 92 (26): 12060–4. Bibcode:1995PNAS...9212060N. doi:10.1073/pnas.92.26.12060. PMC 40296. PMID 8618844.
• Bureau JP, Olink-Coux M, Brouard N, Bayle-Julien S, Huesca M, Herzberg M, Scherrer K (February 1997). "Characterization of prosomes in human lymphocyte subpopulations and their presence as surface antigens". Experimental Cell Research. 231 (1): 50–60. doi:10.1006/excr.1996.3453. PMID 9056411.
• Seeger M, Ferrell K, Frank R, Dubiel W (March 1997). "HIV-1 tat inhibits the 20 S proteasome and its 11 S regulator-mediated activation". The Journal of Biological Chemistry. 272 (13): 8145–8. doi:10.1074/jbc.272.13.8145. PMID 9079628.
• Gerards WL, de Jong WW, Bloemendal H, Boelens W (January 1998). "The human proteasomal subunit HsC8 induces ring formation of other alpha-type subunits". Journal of Molecular Biology. 275 (1): 113–21. doi:10.1006/jmbi.1997.1429. PMID 9451443.
• Henry L, Baz A, Château MT, Caravano R, Scherrer K, Bureau JP (1998). "Proteasome (prosome) subunit variations during the differentiation of myeloid U937 cells". Analytical Cellular Pathology. 15 (3): 131–44. doi:10.1155/1997/869747. PMC 4617585. PMID 9497851.
• Madani N, Kabat D (December 1998). "An endogenous inhibitor of human immunodeficiency virus in human lymphocytes is overcome by the viral Vif protein". Journal of Virology. 72 (12): 10251–5. doi:10.1128/JVI.72.12.10251-10255.1998. PMC 110608. PMID 9811770.
• Simon JH, Gaddis NC, Fouchier RA, Malim MH (December 1998). "Evidence for a newly discovered cellular anti-HIV-1 phenotype". Nature Medicine. 4 (12): 1397–400. doi:10.1038/3987. PMID 9846577.
• Elenich LA, Nandi D, Kent AE, McCluskey TS, Cruz M, Iyer MN, Woodward EC, Conn CW, Ochoa AL, Ginsburg DB, Monaco JJ (September 1999). "The complete primary structure of mouse 20S proteasomes". Immunogenetics. 49 (10): 835–42. doi:10.1007/s002510050562. PMID 10436176.
• Mulder LC, Muesing MA (September 2000). "Degradation of HIV-1 integrase by the N-end rule pathway". The Journal of Biological Chemistry. 275 (38): 29749–53. doi:10.1074/jbc.M004670200. PMID 10893419.
• Kleijnen MF, Shih AH, Zhou P, Kumar S, Soccio RE, Kedersha NL, Gill G, Howley PM (August 2000). "The hPLIC proteins may provide a link between the ubiquitination machinery and the proteasome". Molecular Cell. 6 (2): 409–19. doi:10.1016/S1097-2765(00)00040-X. PMID 10983987.
• Feng Y, Longo DL, Ferris DK (January 2001). "Polo-like kinase interacts with proteasomes and regulates their activity". Cell Growth & Differentiation. 12 (1): 29–37. PMID 11205743.
• Engidawork E, Juranville JF, Fountoulakis M, Dierssen M, Lubec G (2002). Selective upregulation of the ubiquitin-proteasome proteolytic pathway proteins, proteasome zeta chain and isopeptidase T in fetal Down syndrome. Journal of Neural Transmission. Supplementum. pp. 117–30. doi:10.1007/978-3-7091-6262-0_10. ISBN 978-3-211-83704-7. PMID 11771738.
• Sjakste T, Sjakste N, Scherrer K (November 2001). "Exon/intron organisation of human proteasome PROS-27 K gene". DNA Sequence. 12 (4): 261–5. doi:10.3109/10425170109025000. PMID 11924531.