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PSMA1
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 4R3O, 4R67, 1IRU, 5A0Q
Identifiers
Aliases	PSMA1, HC2, HEL-S-275, NU, PROS30, Proteasome (prosome, macropain) subunit, alpha 1, proteasome subunit alpha 1, proteasome 20S subunit alpha 1
External IDs	OMIM: 602854; MGI: 1347005; HomoloGene: 2080; GeneCards: PSMA1; OMA:PSMA1 - orthologs
Gene location (Human) Chr. Chromosome 11 (human) Band 11p15.2 Start 14,504,874 bp End 14,643,635 bp
Gene location (Mouse) Chr. Chromosome 7 (mouse) Band 7 F1|7 59.32 cM Start 113,863,841 bp End 113,875,353 bp
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in islet of Langerhans smooth muscle tissue lymph node rectum appendix endometrium gastrocnemius muscle Descending thoracic aorta right adrenal cortex monocyte Top expressed in otic placode abdominal wall medial ganglionic eminence endocardial cushion mandibular prominence maxillary prominence precursor cell fetal liver hematopoietic progenitor cell migratory enteric neural crest cell efferent ductule More reference expression data BioGPS More reference expression data
Gene ontology Molecular function endopeptidase activity peptidase activity protein binding RNA binding threonine-type endopeptidase activity hydrolase activity lipopolysaccharide binding Cellular component cytoplasm polysome cytosol centrosome nucleoplasm proteasome complex extracellular exosome nucleus proteasome core complex proteasome core complex, alpha-subunit complex 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 immune system process 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 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 protein modification regulation of hematopoietic stem cell differentiation negative regulation of inflammatory response to antigenic stimulus 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 5682 26440 Ensembl ENSG00000129084 ENSMUSG00000030751 UniProt P25786 Q9R1P4 RefSeq (mRNA) NM_148976 NM_001143937 NM_002786 NM_011965 RefSeq (protein) NP_001137409 NP_002777 NP_683877 NP_036095 Location (UCSC) Chr 11: 14.5 – 14.64 Mb Chr 7: 113.86 – 113.88 Mb PubMed search
Wikidata
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Proteasome subunit alpha type-1 is a protein that in humans is encoded by the PSMA1 gene. This protein is one of the 17 essential subunits (alpha subunits 1–7, constitutive beta subunits 1–7, and inducible subunits including beta1i, beta2i, and beta5i) that contributes to the complete assembly of 20S proteasome complex.

Structure

Protein expression

Th gene PSMA1 encodes a member of the peptidase T1A family, that is a 20S core alpha subunit. In a study of mouse gene PSMA1 which share 98% homology with human gene, the gene was isolated and cloned, and then identified as C2 subunit of the 20S proteasome (old nomenclature). The gene has 10 exons that are distributed over a 12kb region on mouse chromosome 7. The same study showed that mouse genes Psma1 and Pde3b are closely linked, residing between cM 53 and 53.3 in a region syntenic to human chromosome 11p15. The human protein proteasome subunit alpha type-1 is also known as 20S proteasome subunit alpha-6 (based on systematic nomenclature). The protein is 30 kDa in size and composed of 263 amino acids. The calculated theoretical pI of this protein is 6.15.

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. Proteasomes are distributed throughout eukaryotic cells at a high concentration and cleave peptides in an ATP/ubiquitin-dependent process in a non-lysosomal pathway.

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. Concomitantly, the rings of alpha subunits form the entrance of substrate entering the proteolytic chamber. In an inactivated 20S proteasome complex, the gate into the internal proteolytic chamber are guarded by N-terminal tails of specific alpha-subunit. 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). As a component of alpha ring, Proteasome subunit alpha type-1 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, 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) 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. 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, cardiovascular diseases, inflammatory responses and autoimmune diseases, and systemic DNA damage responses leading to malignancies.

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

Radiation therapy is a critical modality in the treatment of cancer. Accordingly, the proteasome subunit alpha type-1 was examined as a strategy in radio sensitizing for the treatment of non-small-cell lung carcinomas. Proteasome inhibition through the knockdown of PSMA1 resulted in loss of protein expression of the proteasome subunit alpha type-1 and the proteasome chymotrypsin-like activity. A combination of PSMA1 knockdown in parallel with radiation therapy to treat non-small cell lung carcinoma resulted in an increased sensitivity of the tumor to radiation and improved tumor control. The study suggests that proteasome inhibition through PSMA1 knockdown is a promising strategy for non-small cell lung carcinomas radiosensitization via inhibition of NF-κB-mediated expression of Fanconi anemia/HR DNA repair genes.

References

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7. ^ "Entrez Gene: PSMA1 proteasome (prosome, macropain) subunit, alpha type, 1".
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.
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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. S2CID 16340355.
• Shimbara N, Orino E, Sone S, Ogura T, Takashina M, Shono M, Tamura T, Yasuda H, Tanaka K, Ichihara A (September 1992). "Regulation of gene expression of proteasomes (multi-protease complexes) during growth and differentiation of human hematopoietic cells". The Journal of Biological Chemistry. 267 (25): 18100–9. doi:10.1016/S0021-9258(19)37158-3. PMID 1517242.
• Kanayama H, Tanaka K, Aki M, Kagawa S, Miyaji H, Satoh M, Okada F, Sato S, Shimbara N, Ichihara A (December 1991). "Changes in expressions of proteasome and ubiquitin genes in human renal cancer cells". Cancer Research. 51 (24): 6677–85. PMID 1660345.
• 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.
• 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.
• 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.
• Tipler CP, Hutchon SP, Hendil K, Tanaka K, Fishel S, Mayer RJ (December 1997). "Purification and characterization of 26S proteasomes from human and mouse spermatozoa". Molecular Human Reproduction. 3 (12): 1053–60. doi:10.1093/molehr/3.12.1053. PMID 9464850.
• 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.
• Dahlmann B, Kopp F, Kristensen P, Hendil KB (March 1999). "Identical subunit topographies of human and yeast 20S proteasomes". Archives of Biochemistry and Biophysics. 363 (2): 296–300. doi:10.1006/abbi.1999.1104. PMID 10068451.
• 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.
• Tanahashi N, Murakami Y, Minami Y, Shimbara N, Hendil KB, Tanaka K (May 2000). "Hybrid proteasomes. Induction by interferon-gamma and contribution to ATP-dependent proteolysis". The Journal of Biological Chemistry. 275 (19): 14336–45. doi:10.1074/jbc.275.19.14336. PMID 10799514.
• 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.

• Genes on human chromosome 11