PSMA2

Proteasome subunit alpha 2
PDB rendering based on 1iru.
Available structures PDB Ortholog search: PDBe, RCSB List of PDB id codes 4R3O​, 4R67​
Identifiers
Symbols	PSMA2 ; HC3; MU; PMSA2; PSC2
External IDs	OMIM: 176842 MGI: 104885 HomoloGene: 2081 GeneCards: PSMA2 Gene
EC number	3.4.25.1
Gene ontology Molecular function • endopeptidase activity • threonine-type endopeptidase activity • protein binding Cellular component • proteasome complex • cytoplasmic mRNA processing body • nucleus • nucleoplasm • cytoplasm • cytosol • proteasome core complex • proteasome core complex, alpha-subunit complex • extracellular exosome Biological process • G1/S transition of mitotic cell cycle • protein polyubiquitination • mitotic cell cycle • stimulatory C-type lectin receptor signaling pathway • antigen processing and presentation of peptide antigen via MHC class I • antigen processing and presentation of exogenous peptide antigen via MHC class I, TAP-dependent • regulation of cellular amino acid metabolic process • apoptotic process • DNA damage response, signal transduction by p53 class mediator resulting in cell cycle arrest • response to virus • gene expression • proteasomal ubiquitin-independent protein catabolic process • programmed cell death • viral process • anaphase-promoting complex-dependent proteasomal ubiquitin-dependent protein catabolic process • cellular nitrogen compound metabolic process • antigen processing and presentation of exogenous peptide antigen via MHC class I • regulation of apoptotic process • negative regulation of apoptotic process • proteasome-mediated ubiquitin-dependent protein catabolic process • small molecule metabolic process • innate immune response • negative regulation of ubiquitin-protein ligase activity involved in mitotic cell cycle • positive regulation of ubiquitin-protein ligase activity involved in regulation of mitotic cell cycle transition • regulation of ubiquitin-protein ligase activity involved in mitotic cell cycle • negative regulation of canonical Wnt signaling pathway • positive regulation of canonical Wnt signaling pathway Sources: Amigo / QuickGO
RNA expression pattern
More reference expression data
Orthologs
Species	Human	Mouse
Entrez	5683	19166
Ensembl	ENSG00000106588	ENSMUSG00000015671
UniProt	P25787	P49722
RefSeq (mRNA)	NM_002787	NM_008944
RefSeq (protein)	NP_002778	NP_032970
Location (UCSC)	Chr 7: 42.92 – 42.93 Mb	Chr 13: 14.61 – 14.63 Mb
PubMed search

Proteasome subunit alpha type-2 is a protein that in humans is encoded by the PSMA2 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

Protein expression

The gene PSMA2 encodes a member of the peptidase T1A family, that is a 20S core alpha subunit.^[3] In a study using Fluorescence in situ Hybirdization (FISH), the human gene HC3 (old nomenclature for PMSA2, 4.3kb with 3 exons) was mapped at chromosome band 6q27. The human protein proteasome subunit alpha type-2 is also known as 20S proteasome subunit alpha-2 (based on systematic nomenclature). The protein is 26 kDa in size and composed of 233 amino acids. The calculated theoretical pI of this protein is 7.12.

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.^[4][5]

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.^[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] The eukaryotic proteasome recognized degradable proteins, including damaged proteins for protein quality control purpose or key regulatory protein components for dynamic biological precesses. An essential function of a modified proteasome, the immunoproteasome, is the processing of class I MHC peptides.

As a component of alpha ring, Proteasome subunit alpha type-2 contributes to the formation of heptameric alpha rings and substrate entrance gate. Importantly, alpha2 subunit plays an critical role in the assembly of 19S base and 20S. In a study using Saccharomyces cerevisiae proteasome core particle 20S and regulatory particle 19S (similar to human proteasome) base component to delineate the binding process between 19S and 20S, evidences showed that one 19S subunit, Rpt6, can insert its tail into the pocket formed by alpha2 and alpha3 subunit, facilitating the complex formation between 20S and 19S base component.^[9]

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) ^[10] 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.^[11] 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,^[12][13] cardiovascular diseases,^[14][15][16] inflammatory responses and autoimmune diseases,^[17] and systemic DNA damage responses leading to malignancies.^[18]

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,^[19] Parkinson's disease^[20] and Pick's disease,^[21] Amyotrophic lateral sclerosis (ALS),^[21] Huntington's disease,^[20] Creutzfeldt-Jacob disease,^[22] and motor neuron diseases, polyglutamine (PolyQ) diseases, Muscular dystrophies^[23] and several rare forms of neurodegenerative diseases associated with dementia.^[24] As part of the Ubiquitin-Proteasome System (UPS), the proteasome maintains cardiac protein homeostasis and thus plays a significant role in cardiac Ischemic injury,^[25] ventricular hypertrophy^[26] and Heart failure.^[27] 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.^[28] 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).^[17] 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.^[29] Lastly, autoimmune disease patients with SLE, Sjogren's syndrome and rheumatoid arthritis (RA) predominantly exhibit circulating proteasomes which can be applied as clinical biomarkers.^[30]

References

1. Tamura T, Lee DH, Osaka F, Fujiwara T, Shin S, Chung CH, Tanaka K, Ichihara A (May 1991). "Molecular cloning and sequence analysis of cDNAs for five major subunits of human proteasomes (multi-catalytic proteinase complexes)". Biochimica et Biophysica Acta 1089 (1): 95–102. doi:10.1016/0167-4781(91)90090-9. PMID 2025653.
2. DeMartino GN, Orth K, McCullough ML, Lee LW, Munn TZ, Moomaw CR, Dawson PA, Slaughter CA (Aug 1991). "The primary structures of four subunits of the human, high-molecular-weight proteinase, macropain (proteasome), are distinct but homologous". Biochimica et Biophysica Acta 1079 (1): 29–38. doi:10.1016/0167-4838(91)90020-Z. PMID 1888762.
3. "Entrez Gene: PSMA2 proteasome (prosome, macropain) subunit, alpha type, 2".
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. 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.
6. Groll M, Ditzel L, Löwe J, Stock D, Bochtler M, Bartunik HD, Huber R (Apr 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.
7. Groll M, Bajorek M, Köhler A, Moroder L, Rubin DM, Huber R, Glickman MH, Finley D (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 (Aug 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.
9. Park S, Li X, Kim HM, Singh CR, Tian G, Hoyt MA, Lovell S, Battaile KP, Zolkiewski M, Coffino P, Roelofs J, Cheng Y, Finley D (May 2013). "Reconfiguration of the proteasome during chaperone-mediated assembly". Nature 497 (7450): 512–6. Bibcode:2013Natur.497..512P. doi:10.1038/nature12123. PMC 3687086. PMID 23644457.
10. 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. PMC 4037451. PMID 24457024.
11. Goldberg AL, Stein R, Adams J (Aug 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.
12. 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.
13. 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.
14. 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. PMC 4011959. PMID 24380730.
15. 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. PMC 4241867. PMID 25133688.
16. 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. PMC 4317573. PMID 25651176.
17. Karin M, Delhase M (Feb 2000). "The I kappa B kinase (IKK) and NF-kappa B: key elements of proinflammatory signalling". Seminars in Immunology 12 (1): 85–98. doi:10.1006/smim.2000.0210. PMID 10723801.
18. Ermolaeva MA, Dakhovnik A, Schumacher B (Jan 2015). "Quality control mechanisms in cellular and systemic DNA damage responses". Ageing Research Reviews 23 (Pt A): 3–11. doi:10.1016/j.arr.2014.12.009. PMID 25560147.
19. Checler F, da Costa CA, Ancolio K, Chevallier N, Lopez-Perez E, Marambaud P (Jul 2000). "Role of the proteasome in Alzheimer's disease". Biochimica et Biophysica Acta 1502 (1): 133–8. doi:10.1016/s0925-4439(00)00039-9. PMID 10899438.
20. Chung KK, Dawson VL, Dawson TM (Nov 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.
21. Ikeda, Kenji; Akiyama, Haruhiko; Arai, Tetsuaki; Ueno, Hideki; Tsuchiya, Kuniaki; Kosaka, Kenji (2002). "Morphometrical reappraisal of motor neuron system of Pick's disease and amyotrophic lateral sclerosis with dementia". Acta Neuropathologica 104 (1): 21–28. doi:10.1007/s00401-001-0513-5. ISSN 0001-6322. PMID 12070660.
22. 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.
23. Mathews KD, Moore SA (Jan 2003). "Limb-girdle muscular dystrophy". Current Neurology and Neuroscience Reports 3 (1): 78–85. doi:10.1007/s11910-003-0042-9. PMID 12507416.
24. Mayer RJ (Mar 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.
25. Calise J, Powell SR (Feb 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.
26. Predmore JM, Wang P, Davis F, Bartolone S, Westfall MV, Dyke DB, Pagani F, Powell SR, Day SM (Mar 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.
27. Powell SR (Jul 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.
28. Adams J (Apr 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.
29. Ben-Neriah Y (Jan 2002). "Regulatory functions of ubiquitination in the immune system". Nature Immunology 3 (1): 20–6. doi:10.1038/ni0102-20. PMID 11753406.
30. Egerer K, Kuckelkorn U, Rudolph PE, Rückert JC, Dörner T, Burmester GR, Kloetzel PM, Feist E (Oct 2002). "Circulating proteasomes are markers of cell damage and immunologic activity in autoimmune diseases". The Journal of Rheumatology 29 (10): 2045–52. PMID 12375310.

Further reading

• 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.
• Goff SP (Aug 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.
• Okumura K, Nogami M, Taguchi H, Hisamatsu H, Tanaka K (May 1995). "The genes for the alpha-type HC3 (PMSA2) and beta-type HC5 (PMSB1) subunits of human proteasomes map to chromosomes 6q27 and 7p12-p13 by fluorescence in situ hybridization". Genomics 27 (2): 377–9. doi:10.1006/geno.1995.1062. PMID 7558012.
• Kristensen P, Johnsen AH, Uerkvitz W, Tanaka K, Hendil KB (Dec 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.
• Tamura T, Osaka F, Kawamura Y, Higuti T, Ishida N, Nothwang HG, Tsurumi C, Tanaka K, Ichihara A (Nov 1994). "Isolation and characterization of alpha-type HC3 and beta-type HC5 subunit genes of human proteasomes". Journal of Molecular Biology 244 (1): 117–24. doi:10.1006/jmbi.1994.1710. PMID 7966316.
• Maruyama K, Sugano S (Jan 1994). "Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides". Gene 138 (1–2): 171–4. doi:10.1016/0378-1119(94)90802-8. PMID 8125298.
• Knuehl C, Seelig A, Brecht B, Henklein P, Kloetzel PM (May 1996). "Functional analysis of eukaryotic 20S proteasome nuclear localization signal". Experimental Cell Research 225 (1): 67–74. doi:10.1006/excr.1996.0157. PMID 8635518.
• Seeger M, Ferrell K, Frank R, Dubiel W (Mar 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.
• Suzuki Y, Yoshitomo-Nakagawa K, Maruyama K, Suyama A, Sugano S (Oct 1997). "Construction and characterization of a full length-enriched and a 5'-end-enriched cDNA library". Gene 200 (1–2): 149–56. doi:10.1016/S0378-1119(97)00411-3. PMID 9373149.
• Madani N, Kabat D (Dec 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. PMC 110608. PMID 9811770.
• Simon JH, Gaddis NC, Fouchier RA, Malim MH (Dec 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 (Sep 1999). "The complete primary structure of mouse 20S proteasomes". Immunogenetics 49 (10): 835–42. doi:10.1007/s002510050562. PMID 10436176.
• Mulder LC, Muesing MA (Sep 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 (Aug 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.
• Sheehy AM, Gaddis NC, Choi JD, Malim MH (Aug 2002). "Isolation of a human gene that inhibits HIV-1 infection and is suppressed by the viral Vif protein". Nature 418 (6898): 646–50. Bibcode:2002Natur.418..646S. doi:10.1038/nature00939. PMID 12167863.
• Huang X, Seifert U, Salzmann U, Henklein P, Preissner R, Henke W, Sijts AJ, Kloetzel PM, Dubiel W (Nov 2002). "The RTP site shared by the HIV-1 Tat protein and the 11S regulator subunit alpha is crucial for their effects on proteasome function including antigen processing". Journal of Molecular Biology 323 (4): 771–82. doi:10.1016/S0022-2836(02)00998-1. PMID 12419264.
• Bommel H, Xie G, Rossoll W, Wiese S, Jablonka S, Boehm T, Sendtner M (Nov 2002). "Missense mutation in the tubulin-specific chaperone E (Tbce) gene in the mouse mutant progressive motor neuronopathy, a model of human motoneuron disease". The Journal of Cell Biology 159 (4): 563–9. doi:10.1083/jcb.200208001. PMC 2173089. PMID 12446740.