PSMA6 | |||||||||||||||||||||||||||||||||||||||||||||||||||
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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; OMA:PSMA6 - orthologs | ||||||||||||||||||||||||||||||||||||||||||||||||||
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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.
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.[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
[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.[7][8]
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.[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
[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) [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
[edit]PSMA6 has been shown to interact with PLK1[34] and PSMA3.[35][36]
References
[edit]- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000021024 – Ensembl, May 2017
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- ^ 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.
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- ^ 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. S2CID 5780576.
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- ^ 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.
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- ^ a b 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. S2CID 20484541.
- ^ 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.
- ^ 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. S2CID 8235923.
- ^ 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. hdl:2066/29386. PMID 9451443.
Further reading
[edit]- 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. S2CID 16340355.
- 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. S2CID 37906146.
- 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. hdl:2066/29386. 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. S2CID 25235070.
- 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. S2CID 20977116.
- 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 (2001). "Selective upregulation of the ubiquitin-proteasome proteolytic pathway proteins, proteasome zeta chain and isopeptidase T in fetal Down syndrome". Protein Expression in Down Syndrome Brain. pp. 117–30. doi:10.1007/978-3-7091-6262-0_10. ISBN 978-3-211-83704-7. PMID 11771738.
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ignored (help) - 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. S2CID 45201189.