1. Function

2. Structure
     Complex assembly  

3. Mechanism

4. Clinical significance

5. Interactions

6. References

7. Further reading

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.^[1][2] 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-3 contributes to the formation of heptameric alpha rings and substrate entrance gate.

Structure

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.^[3]

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]

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.^[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]

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.

The proteasomes form a pivotal component for the Ubiquitin-Proteasome System (UPS) ^[9] 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.^[10] 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,^[11][12] cardiovascular diseases,^[13][14][15] inflammatory responses and autoimmune diseases,^[16] and systemic DNA damage responses leading to malignancies.^[17]

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,^[18] Parkinson's disease^[19] and Pick's disease,^[20] Amyotrophic lateral sclerosis (ALS),^[20] Huntington's disease,^[19] Creutzfeldt–Jakob disease,^[21] and motor neuron diseases, polyglutamine (PolyQ) diseases, Muscular dystrophies^[22] and several rare forms of neurodegenerative diseases associated with dementia.^[23] As part of the Ubiquitin-Proteasome System (UPS), the proteasome maintains cardiac protein homeostasis and thus plays a significant role in cardiac Ischemic injury,^[24] ventricular hypertrophy^[25] and Heart failure.^[26] 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.^[27] 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).^[16] 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.^[28] Lastly, autoimmune disease patients with SLE, Sjogren's syndrome and rheumatoid arthritis (RA) predominantly exhibit circulating proteasomes which can be applied as clinical biomarkers.^[29]

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.^[30]

Interactions

PSMA3 has been shown to interact with

• CRYAB,^[31]
• PLK1,^[32]
• PSMA6,^[33][34] and
• Zif268.^[35]

References

Further reading

• {{cite journal | vauthors = Goff SP | title = Death by deamination: a novel host restriction system for HIV-1 | journal = Cell | volume = 114 | issue = 3 | pages = 281–3 | date = August 2003 | pmid = 12914693 | doi = 10.1016/S0092-8674(03)00602-0 }}
• {{cite journal | vauthors = Kristensen P, Johnsen AH, Uerkvitz W, Tanaka K, Hendil KB | title = Human proteasome subunits from 2-dimensional gels identified by partial sequencing | journal = Biochemical and Biophysical Research Communications | volume = 205 | issue = 3 | pages = 1785–9 | date = December 1994 | pmid = 7811265 | doi = 10.1006/bbrc.1994.2876 }}
• {{cite journal | vauthors = Akioka H, Forsberg NE, Ishida N, Okumura K, Nogami M, Taguchi H, Noda C, Tanaka K | title = Isolation and characterization of the HC8 subunit gene of the human proteasome | journal = Biochemical and Biophysical Research Communications | volume = 207 | issue = 1 | pages = 318–23 | date = February 1995 | pmid = 7857283 | doi = 10.1006/bbrc.1995.1190 }}
• {{cite journal | vauthors = Castaño JG, Mahillo E, Arizti P, Arribas J | title = Phosphorylation of C8 and C9 subunits of the multicatalytic proteinase by casein kinase II and identification of the C8 phosphorylation sites by direct mutagenesis | journal = Biochemistry | volume = 35 | issue = 12 | pages = 3782–9 | date = March 1996 | pmid = 8619999 | doi = 10.1021/bi952540s }}
• {{cite journal | vauthors = Seeger M, Ferrell K, Frank R, Dubiel W | title = HIV-1 tat inhibits the 20 S proteasome and its 11 S regulator-mediated activation | journal = The Journal of Biological Chemistry | volume = 272 | issue = 13 | pages = 8145–8 | date = March 1997 | pmid = 9079628 | doi = 10.1074/jbc.272.13.8145 }}
• {{cite journal | vauthors = Gerards WL, de Jong WW, Bloemendal H, Boelens W | title = The human proteasomal subunit HsC8 induces ring formation of other alpha-type subunits | journal = Journal of Molecular Biology | volume = 275 | issue = 1 | pages = 113–21 | date = January 1998 | pmid = 9451443 | doi = 10.1006/jmbi.1997.1429 }}
• {{cite journal | vauthors = Madani N, Kabat D | title = An endogenous inhibitor of human immunodeficiency virus in human lymphocytes is overcome by the viral Vif protein | journal = Journal of Virology | volume = 72 | issue = 12 | pages = 10251–5 | date = December 1998 | pmid = 9811770 | pmc = 110608 | doi = }}
• {{cite journal | vauthors = Simon JH, Gaddis NC, Fouchier RA, Malim MH | title = Evidence for a newly discovered cellular anti-HIV-1 phenotype | journal = Nature Medicine | volume = 4 | issue = 12 | pages = 1397–400 | date = December 1998 | pmid = 9846577 | doi = 10.1038/3987 }}
• {{cite journal | vauthors = Mulder LC, Muesing MA | title = Degradation of HIV-1 integrase by the N-end rule pathway | journal = The Journal of Biological Chemistry | volume = 275 | issue = 38 | pages = 29749–53 | date = September 2000 | pmid = 10893419 | doi = 10.1074/jbc.M004670200 }}
• {{cite journal | vauthors = Connell P, Ballinger CA, Jiang J, Wu Y, Thompson LJ, Höhfeld J, Patterson C | title = The co-chaperone CHIP regulates protein triage decisions mediated by heat-shock proteins | journal = Nature Cell Biology | volume = 3 | issue = 1 | pages = 93–6 | date = January 2001 | pmid = 11146632 | doi = 10.1038/35050618 }}
• {{cite journal | vauthors = Feng Y, Longo DL, Ferris DK | title = Polo-like kinase interacts with proteasomes and regulates their activity | journal = Cell Growth & Differentiation | volume = 12 | issue = 1 | pages = 29–37 | date = January 2001 | pmid = 11205743 | doi = }}
• {{cite journal | vauthors = Boelens WC, Croes Y, de Jong WW | title = Interaction between alphaB-crystallin and the human 20S proteasomal subunit C8/alpha7 | journal = Biochimica et Biophysica Acta | volume = 1544 | issue = 1–2 | pages = 311–9 | date = January 2001 | pmid = 11341940 | doi = 10.1016/S0167-4838(00)00243-0 }}
• {{cite journal | vauthors = Touitou R, Richardson J, Bose S, Nakanishi M, Rivett J, Allday MJ | title = A degradation signal located in the C-terminus of p21WAF1/CIP1 is a binding site for the C8 alpha-subunit of the 20S proteasome | journal = The EMBO Journal | volume = 20 | issue = 10 | pages = 2367–75 | date = May 2001 | pmid = 11350925 | pmc = 125454 | doi = 10.1093/emboj/20.10.2367 }}
• {{cite journal | vauthors = Sheehy AM, Gaddis NC, Choi JD, Malim MH | title = Isolation of a human gene that inhibits HIV-1 infection and is suppressed by the viral Vif protein | journal = Nature | volume = 418 | issue = 6898 | pages = 646–50 | date = August 2002 | pmid = 12167863 | doi = 10.1038/nature00939 | bibcode = 2002Natur.418..646S }}
• {{cite journal | vauthors = Claverol S, Burlet-Schiltz O, Girbal-Neuhauser E, Gairin JE, Monsarrat B | title = Mapping and structural dissection of human 20 S proteasome using proteomic approaches | journal = Molecular & Cellular Proteomics | volume = 1 | issue = 8 | pages = 567–78 | date = August 2002 | pmid = 12376572 | doi = 10.1074/mcp.M200030-MCP200 }}
• {{cite journal | vauthors = Bae MH, Jeong CH, Kim SH, Bae MK, Jeong JW, Ahn MY, Bae SK, Kim ND, Kim CW, Kim KR, Kim KW | title = Regulation of Egr-1 by association with the proteasome component C8 | journal = Biochimica et Biophysica Acta | volume = 1592 | issue = 2 | pages = 163–7 | date = October 2002 | pmid = 12379479 | doi = 10.1016/S0167-4889(02)00310-5 }}
• {{cite journal | vauthors = Huang X, Seifert U, Salzmann U, Henklein P, Preissner R, Henke W, Sijts AJ, Kloetzel PM, Dubiel W | title = 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 = Journal of Molecular Biology | volume = 323 | issue = 4 | pages = 771–82 | date = November 2002 | pmid = 12419264 | doi = 10.1016/S0022-2836(02)00998-1 }}

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