PSMA3

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PSMA3
Protein PSMA3 PDB 1iru.png
Available structures
PDB Ortholog search: PDBe RCSB
Identifiers
Aliases PSMA3, HC8, PSC3, proteasome subunit alpha 3
External IDs MGI: 104883 HomoloGene: 2082 GeneCards: PSMA3
RNA expression pattern
PBB GE PSMA3 201532 at fs.png
More reference expression data
Orthologs
Species Human Mouse
Entrez
Ensembl
UniProt
RefSeq (mRNA)

NM_002788
NM_152132

NM_011184
NM_001310595
NM_001310596

RefSeq (protein)

NP_002779
NP_687033

NP_035314.3
NP_001297524
NP_001297525
NP_035314

Location (UCSC) Chr 14: 58.24 – 58.27 Mb Chr 12: 70.97 – 71 Mb
PubMed search [1] [2]
Wikidata
View/Edit Human View/Edit Mouse

Proteasome subunit alpha type-3 also known as macropain subunit C8 and proteasome component C8 is a protein that in humans is encoded by the PSMA3 gene.[3][4] 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[edit]

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-3 contributes to the formation of heptameric alpha rings and substrate entrance gate.

Structure[edit]

The human protein proteasome subunit alpha type-3 is 28.4 kDa in size and composed of 254 amino acids. The calculated theoretical pI of this protein is 5.08.[5]

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.[6][7]

Mechanism[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.[7] 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.[8][9] 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.[9][10]

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) [11] 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.[12] 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,[13][14] cardiovascular diseases,[15][16][17] inflammatory responses and autoimmune diseases,[18] and systemic DNA damage responses leading to malignancies.[19]

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,[20] Parkinson's disease[21] and Pick's disease,[22] Amyotrophic lateral sclerosis (ALS),[22] Huntington's disease,[21] Creutzfeldt–Jakob disease,[23] and motor neuron diseases, polyglutamine (PolyQ) diseases, Muscular dystrophies[24] and several rare forms of neurodegenerative diseases associated with dementia.[25] As part of the Ubiquitin-Proteasome System (UPS), the proteasome maintains cardiac protein homeostasis and thus plays a significant role in cardiac Ischemic injury,[26] ventricular hypertrophy[27] and Heart failure.[28] 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.[29] 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).[30] 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, Sjogren's syndrome and rheumatoid arthritis (RA) predominantly exhibit circulating proteasomes which can be applied as clinical biomarkers.[32]

A role of the proteasome subunit alpha type-3 has been linked in underlying mechanisms of human malignancies. It has been suggested that Cables1 as a novel p21 regulator through maintaining p21 stability and supporting the model that the tumor-suppressive function of Cables1 occurs at least in part through enhancing the tumor-suppressive activity of p21. In this process, Cables 1 mechanistically interferes the proteasome subunit alpha type-3 (PMSA3) hereby binding to p21 to induce cell death and inhibit cell proliferation.[33]

Interactions[edit]

PSMA3 has been shown to interact with

References[edit]

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  2. ^ "Mouse PubMed Reference:". 
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  4. ^ Coux O, Tanaka K, Goldberg AL (Nov 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. ^ Kozlowski LP (October 2016). "IPC - Isoelectric Point Calculator". Biology Direct. 11 (1): 55. doi:10.1186/s13062-016-0159-9. PMC 5075173Freely accessible. PMID 27769290. 
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  10. ^ 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. 
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  28. ^ Powell SR (July 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. 
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  33. ^ Shi Z, Li Z, Li ZJ, Cheng K, Du Y, Fu H, Khuri FR (May 2015). "Cables1 controls p21/Cip1 protein stability by antagonizing proteasome subunit alpha type 3". Oncogene. 34 (19): 2538–45. doi:10.1038/onc.2014.171. PMID 24975575. 
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Further reading[edit]