PSMA7

PSMA7
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 4R3O, 4R67, 1IRU, 5A0Q
Identifiers
Aliases	PSMA7, C6, HSPC, RC6-1, XAPC7, HEL-S-276, proteasome subunit alpha 7, proteasome 20S subunit alpha 7
External IDs	OMIM: 606607; MGI: 1347070; HomoloGene: 105299; GeneCards: PSMA7; OMA:PSMA7 - orthologs
Gene location (Human) Chr. Chromosome 20 (human)[1] Band 20q13.33 Start 62,136,733 bp[1] End 62,143,440 bp[1]
Gene location (Mouse) Chr. Chromosome 2 (mouse)[2] Band 2|2 H4 Start 179,678,167 bp[2] End 179,684,226 bp[2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in gastrocnemius muscle oocyte right adrenal gland left adrenal gland left coronary artery right lung gastric mucosa left uterine tube upper lobe of left lung right coronary artery Top expressed in blastocyst endocardial cushion morula maxillary prominence abdominal wall medial ganglionic eminence atrioventricular valve lip somite seminal vesicula More reference expression data BioGPS More reference expression data
Gene ontology Molecular function endopeptidase activity peptidase activity protein binding identical protein binding threonine-type endopeptidase activity hydrolase activity Cellular component cytoplasm cytosol nucleoplasm proteasome complex extracellular exosome nucleus proteasome core complex postsynapse 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 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 viral 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 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 5688 26444 Ensembl ENSG00000101182 ENSMUSG00000027566 UniProt O14818 Q9Z2U0 RefSeq (mRNA) NM_152255 NM_002792 NM_001289476 NM_011969 RefSeq (protein) NP_002783 NP_001276405 NP_036099 Location (UCSC) Chr 20: 62.14 – 62.14 Mb Chr 2: 179.68 – 179.68 Mb PubMed search [3] [4]
Wikidata
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Proteasome subunit alpha type-7 also known as 20S proteasome subunit alpha-4 is a protein that in humans is encoded by the PSMA7 gene.^[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.

Function

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. As a component of alpha ring, proteasome subunit alpha type-7 contributes to the formation of heptameric alpha rings and substrate entrance gate. Importantly, this subunit plays a critical role in the assembly of 19S base and 20S. This particular subunit has been shown to interact specifically with the hepatitis B virus X protein, a protein critical to viral replication. In addition, this subunit is involved in regulating hepatitis virus C internal ribosome entry site (IRES) activity, an activity essential for viral replication. This core alpha subunit is also involved in regulating the hypoxia-inducible factor-1alpha, a transcription factor important for cellular responses to oxygen tension. Recent study on underlying mechanisms of E3 ligase Parkin-related neurodegeneration identified this proteasome subunit as one of Parkin associating partner. The protein-protein interaction was initiated between the C-terminal domain of Parkin and C-terminal of subunit alpha4 (systematic nomenclature).^[7]

Structure

Expression

The gene PSMA7 encodes a member of the peptidase T1A family, that is a 20S core alpha subunit. This gene has 7 exons and locates at a chromosome band 20q13.33. Multiple isoforms of this subunit arising from alternative splicing may exist but alternative transcripts for only two isoforms have been defined. A pseudogene has been identified on chromosome 9.^[6]

The human protein Proteasome subunit alpha type-7 is 28 kDa in size and composed of 248 amino acids. The calculated theoretical pI (Isoelectric point) of this protein is 8.60.

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]

Mechanism

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]

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) ^[13] 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.^[14] 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,^[15][16] cardiovascular diseases,^[17][18][19] inflammatory responses and autoimmune diseases,^[20] and systemic DNA damage responses leading to malignancies.^[21]

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,^[22] Parkinson's disease^[23] and Pick's disease,^[24] Amyotrophic lateral sclerosis (ALS),^[24] Huntington's disease,^[23] Creutzfeldt–Jakob disease,^[25] and motor neuron diseases, polyglutamine (PolyQ) diseases, Muscular dystrophies^[26] and several rare forms of neurodegenerative diseases associated with dementia.^[27] As part of the ubiquitin–proteasome system (UPS), the proteasome maintains cardiac protein homeostasis and thus plays a significant role in cardiac ischemic injury,^[28] ventricular hypertrophy^[29] and heart failure.^[30] 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.^[31] 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).^[20] 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.^[32] Lastly, autoimmune disease patients with SLE, Sjögren syndrome and rheumatoid arthritis (RA) predominantly exhibit circulating proteasomes which can be applied as clinical biomarkers.^[33]

Reports have shown that the proteasome subunit alpha type-7 (PSMA7) is overexpressed in colorectal cancer and associated with its hepatic metastasis.^[34][35] It was further reported that PSMA7 is associated with nucleotide-binding oligomerization domain-containing protein 1 (NOD1) as a negative regulator and may promote tumor growth by its inhibitory role on NOD1.^[36]

Interactions

PSMA7 has been shown to interact with HIF1A^[37] and PLK1.^[38]

References

Further reading