PSMA2

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

PSMA2
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 4R3O, 4R67, 5A0Q
Identifiers
Aliases	PSMA2, HC3, MU, PMSA2, PSC2, proteasome subunit alpha 2, proteasome 20S subunit alpha 2
External IDs	OMIM: 176842 MGI: 104885 HomoloGene: 2081 GeneCards: PSMA2
Gene location (Human) Chr. Chromosome 7 (human)[1] Band 7p14.1 Start 42,916,861 bp[1] End 42,932,185 bp[1]
RNA expression pattern More reference expression data
Gene ontology Molecular function • endopeptidase activity • peptidase activity • GO:0001948 protein binding • threonine-type endopeptidase activity • hydrolase activity Cellular component • cytoplasm • cytosol • nucleoplasm • proteasome complex • extracellular exosome • cell nucleus • proteasome core complex • extracellular region • secretory granule lumen • ficolin-1-rich granule lumen • proteasome core complex, alpha-subunit complex • P-body Biological process • regulation of cellular amino acid metabolic process • antigen processing and presentation of exogenous peptide antigen via MHC class I, TAP-dependent • regulation of mRNA stability • ubiquitin-dependent protein catabolic process • positive regulation of canonical Wnt signaling pathway • response to virus • 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 • 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 • neutrophil degranulation • 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	5683	19166
Ensembl	ENSG00000106588	n/a
UniProt	P25787	P49722
RefSeq (mRNA)	NM_002787	NM_008944
RefSeq (protein)	NP_002778	NP_032970
Location (UCSC)	Chr 7: 42.92 – 42.93 Mb	n/a
PubMed search	[2]	[3]
Wikidata
View/Edit Human View/Edit Mouse

Structure

Protein expression

The gene PSMA2 encodes a member of the peptidase T1A family, that is a 20S core alpha subunit.[6] Using 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 25.9 kDa in size and composed of 234 amino acids. The calculated theoretical pI of this protein is 6.77.[7]

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.[8][9]

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.[9] 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.[10][11] 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.[11][12] 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.[13]

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) [14] 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.[15] 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,[16][17] cardiovascular diseases,[18][19][20] inflammatory responses and autoimmune diseases,[21] and systemic DNA damage responses leading to malignancies.[22]

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,[23] Parkinson's disease[24] and Pick's disease,[25] Amyotrophic lateral sclerosis (ALS),[25] Huntington's disease,[24] Creutzfeldt–Jakob disease,[26] and motor neuron diseases, polyglutamine (PolyQ) diseases, Muscular dystrophies[27] and several rare forms of neurodegenerative diseases associated with dementia.[28] As part of the ubiquitin–proteasome system (UPS), the proteasome maintains cardiac protein homeostasis and thus plays a significant role in cardiac ischemic injury,[29] ventricular hypertrophy[30] and heart failure.[31] 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.[32] 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).[21] 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.[33] Lastly, autoimmune disease patients with SLE, Sjögren syndrome and rheumatoid arthritis (RA) predominantly exhibit circulating proteasomes which can be applied as clinical biomarkers.[34]

References

1. GRCh38: Ensembl release 89: ENSG00000106588 - 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. DeMartino GN, Orth K, McCullough ML, Lee LW, Munn TZ, Moomaw CR, Dawson PA, Slaughter CA (August 1991). "The primary structures of four subunits of the human, high-molecular-weight proteinase, macropain (proteasome), are distinct but homologous". Biochimica et Biophysica Acta (BBA) - Protein Structure and Molecular Enzymology. 1079 (1): 29–38. doi:10.1016/0167-4838(91)90020-Z. PMID 1888762.
6. "Entrez Gene: PSMA2 proteasome (prosome, macropain) subunit, alpha type, 2".
7. Kozlowski LP (October 2016). "IPC - Isoelectric Point Calculator". Biology Direct. 11 (1): 55. doi:10.1186/s13062-016-0159-9. PMC 5075173. PMID 27769290. Archived from the original on 2013-04-29. Retrieved 2020-04-28.
8. 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.
9. 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.
10. 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.
11. 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.
12. 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.
13. 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.
14. 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.
15. 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.
16. 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.
17. 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.
18. 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.
19. 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.
20. 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.
21. 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. doi:10.1006/smim.2000.0210. PMID 10723801.
22. Ermolaeva MA, Dakhovnik A, Schumacher B (September 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. PMC 4886828. PMID 25560147.
23. 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.
24. 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.
25. 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.
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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 (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.
• 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 (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.
• Tamura T, Osaka F, Kawamura Y, Higuti T, Ishida N, Nothwang HG, Tsurumi C, Tanaka K, Ichihara A (November 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 (January 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 (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.
• Suzuki Y, Yoshitomo-Nakagawa K, Maruyama K, Suyama A, Sugano S (October 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 (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.
• Sheehy AM, Gaddis NC, Choi JD, Malim MH (August 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 (November 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 (November 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.