PSMB4

Proteasome subunit beta type-4 also known as 20S proteasome subunit beta-7 (based on systematic nomenclature) is a protein that in humans is encoded by the PSMB4 gene.[4]

PSMB4
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 4R3O, 4R67, 5A0Q
Identifiers
Aliases	PSMB4, HN3, HsN3, PROS-26, PROS26, proteasome subunit beta 4, PRAAS3, proteasome 20S subunit beta 4
External IDs	OMIM: 602177 MGI: 1098257 HomoloGene: 2090 GeneCards: PSMB4
Gene location (Human) Chr. Chromosome 1 (human)[1] Band 1q21.3 Start 151,399,560 bp[1] End 151,401,937 bp[1]
RNA expression pattern More reference expression data
Gene ontology Molecular function • endopeptidase activity • lipopolysaccharide binding • 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 • proteasome core complex, beta-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 • 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 • MAPK cascade • proteolysis • Fc-epsilon receptor signaling pathway • NIK/NF-kappaB signaling • negative regulation of inflammatory response to antigenic stimulus • 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 • GO:0022415 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 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	5692	19172
Ensembl	ENSG00000159377	ENSMUSG00000005779
UniProt	P28070	P99026
RefSeq (mRNA)	NM_002796	NM_008945
RefSeq (protein)	NP_002787	NP_032971
Location (UCSC)	Chr 1: 151.4 – 151.4 Mb	n/a
PubMed search	[2]	[3]
Wikidata
View/Edit Human View/Edit Mouse

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. In particular, proteasome subunit beta type-2, along with other beta subunits, assemble into two heptameric rings and subsequently a proteolytic chamber for substrate degradation. 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.

Structure

Gene

This gene PSMB4 encodes a member of the proteasome B-type family, also known as the T1B family, that is a 20S core beta subunit.[5] The gene has 7 exons and locates at chromosome band 1q21.

Protein

The human protein proteasome subunit beta type-2 is 23 kDa in size and composed of 219 amino acids. The calculated theoretical pI of this protein is 5.47.

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.[6][7]

Function

Protein functions are supported by its tertiary structure and its interaction with associating partners. As one of 28 subunits of 20S proteasome, protein proteasome subunit beta type-4 contributes to form a proteolytic environment for substrate degradation. Evidences of the 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. This unique structure design prevents random encounter between proteolytic active sites and protein substrate, which makes protein degradation a well-regulated process.[8][9] 20S proteasome complex, by itself, is usually functionally inactive. 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

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. Recently, more effort has also 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, Creutzfeldt–Jakob disease, and motor neuron diseases, polyglutamine (PolyQ) diseases, Muscular dystrophies[23] and several rare forms of neurodegenerative diseases associated with dementia.[24] As part of the ubiquitin–proteasome system (UPS), the proteasome maintains cardiac protein homeostasis and thus plays a significant role in cardiac ischemic injury,[25] ventricular hypertrophy[26] and heart failure.[27] 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.[28] 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).[18] 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.[29] Lastly, autoimmune disease patients with SLE, Sjögren syndrome and rheumatoid arthritis (RA) predominantly exhibit circulating proteasomes which can be applied as clinical biomarkers.[30]

Proteasomal subunit PSMB4 (proteasome subunit beta type-4 also known as 20S proteasome subunit beta-7) has been suggested as a survival gene in an animal model of hepatocellular carcinoma and in glioblastoma cell lines. Additionally, gene expression levels of proteasomal subunits (PSMA1, PSMA5, PSMB4, PSMB5 and PSMD1) were investigated in 80 neuroendocrine pulmonary tumors and compared to controls and it was further revealed tha PSMB4 mRNA was significantly associated with the proliferative activity of neuroendocrine pulmonary tumors.[31] Thus far, it appears that PSMB4 may have significant roles in underlying processes and mechanisms of malignancies.

Interactions

PSMB4 has been shown to interact with Mothers against decapentaplegic homolog 1.[32][33]

References

1. GRCh38: Ensembl release 89: ENSG00000159377 - 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.
4. Nothwang HG, Tamura T, Tanaka K, Ichihara A (Nov 1994). "Sequence analyses and inter-species comparisons of three novel human proteasomal subunits, HsN3, HsC7-I and HsC10-II, confine potential proteolytic active-site residues". Biochim Biophys Acta. 1219 (2): 361–8. doi:10.1016/0167-4781(94)90060-4. PMID 7918633.
5. "Entrez Gene: PSMB4 proteasome (prosome, macropain) subunit, beta type, 4".
6. 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.
7. 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.
8. Groll M, Ditzel L, Löwe J, Stock D, Bochtler M, Bartunik HD, Huber R (Apr 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.
9. Groll M, Bajorek M, Köhler A, Moroder L, Rubin DM, Huber R, Glickman MH, Finley D (Nov 2000). "A gated channel into the proteasome core particle". Nature Structural Biology. 7 (11): 1062–7. doi:10.1038/80992. PMID 11062564.
10. Zong C, Gomes AV, Drews O, Li X, Young GW, Berhane B, Qiao X, French SW, Bardag-Gorce F, Ping P (Aug 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.
11. Kleiger G, Mayor T (Jun 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.
12. Goldberg AL, Stein R, Adams J (Aug 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.
13. Sulistio YA, Heese K (Jan 2015). "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.
14. 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.
15. Sandri M, Robbins J (Jun 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.
16. Drews O, Taegtmeyer H (Dec 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.
17. Wang ZV, Hill JA (Feb 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.
18. Karin M, Delhase M (Feb 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.
19. Ermolaeva MA, Dakhovnik A, Schumacher B (Jan 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.
20. Checler F, da Costa CA, Ancolio K, Chevallier N, Lopez-Perez E, Marambaud P (Jul 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.
21. Chung KK, Dawson VL, Dawson TM (Nov 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.
22. Ikeda K, Akiyama H, Arai T, Ueno H, Tsuchiya K, Kosaka K (Jul 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.
23. Mathews KD, Moore SA (Jan 2003). "Limb-girdle muscular dystrophy". Current Neurology and Neuroscience Reports. 3 (1): 78–85. doi:10.1007/s11910-003-0042-9. PMID 12507416.
24. Mayer RJ (Mar 2003). "From neurodegeneration to neurohomeostasis: the role of ubiquitin". Drug News & Perspectives. 16 (2): 103–8. doi:10.1358/dnp.2003.16.2.829327. PMID 12792671.
25. Calise J, Powell SR (Feb 2013). "The ubiquitin proteasome system and myocardial ischemia". American Journal of Physiology. Heart and Circulatory Physiology. 304 (3): H337–49. doi:10.1152/ajpheart.00604.2012. PMC 3774499. PMID 23220331.
26. Predmore JM, Wang P, Davis F, Bartolone S, Westfall MV, Dyke DB, Pagani F, Powell SR, Day SM (Mar 2010). "Ubiquitin proteasome dysfunction in human hypertrophic and dilated cardiomyopathies". Circulation. 121 (8): 997–1004. doi:10.1161/CIRCULATIONAHA.109.904557. PMC 2857348. PMID 20159828.
27. Powell SR (Jul 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.
28. Adams J (Apr 2003). "Potential for proteasome inhibition in the treatment of cancer". Drug Discovery Today. 8 (7): 307–15. doi:10.1016/s1359-6446(03)02647-3. PMID 12654543.
29. Ben-Neriah Y (Jan 2002). "Regulatory functions of ubiquitination in the immune system". Nature Immunology. 3 (1): 20–6. doi:10.1038/ni0102-20. PMID 11753406.
30. Egerer K, Kuckelkorn U, Rudolph PE, Rückert JC, Dörner T, Burmester GR, Kloetzel PM, Feist E (Oct 2002). "Circulating proteasomes are markers of cell damage and immunologic activity in autoimmune diseases". The Journal of Rheumatology. 29 (10): 2045–52. PMID 12375310.
31. Mairinger FD, Walter RF, Theegarten D, Hager T, Vollbrecht C, Christoph DC, Worm K, Ting S, Werner R, Stamatis G, Mairinger T, Baba H, Zarogoulidis K, Huang H, Li Q, Tsakiridis K, Zarogoulidis P, Schmid KW, Wohlschlaeger J (2014). "Gene Expression Analysis of the 26S Proteasome Subunit PSMB4 Reveals Significant Upregulation, Different Expression and Association with Proliferation in Human Pulmonary Neuroendocrine Tumours". Journal of Cancer. 5 (8): 646–54. doi:10.7150/jca.9955. PMC 4142326. PMID 25157275.
32. Lin Y, Martin J, Gruendler C, Farley J, Meng X, Li BY, Lechleider R, Huff C, Kim RH, Grasser WA, Paralkar V, Wang T (Jun 2002). "A novel link between the proteasome pathway and the signal transduction pathway of the bone morphogenetic proteins (BMPs)". BMC Cell Biol. 3: 15. doi:10.1186/1471-2121-3-15. PMC 117437. PMID 12097147.
33. Guo X, Lin Y, Horbinski C, Drahushuk KM, Kim IJ, Kaplan PL, Lein P, Wang T, Higgins D (Aug 2001). "Dendritic growth induced by BMP-7 requires Smad1 and proteasome activity". J. Neurobiol. 48 (2): 120–30. doi:10.1002/neu.1046. PMID 11438941.

Further reading

• Coux O, Tanaka K, Goldberg AL (1996). "Structure and functions of the 20S and 26S proteasomes". Annu. Rev. Biochem. 65 (1): 801–47. doi:10.1146/annurev.bi.65.070196.004101. PMID 8811196.
• Goff SP (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.
• Rasmussen HH, van Damme J, Puype M, Gesser B, Celis JE, Vandekerckhove J (1993). "Microsequences of 145 proteins recorded in the two-dimensional gel protein database of normal human epidermal keratinocytes". Electrophoresis. 13 (12): 960–9. doi:10.1002/elps.11501301199. PMID 1286667.
• Lee LW, Moomaw CR, Orth K, McGuire MJ, DeMartino GN, Slaughter CA (1990). "Relationships among the subunits of the high molecular weight proteinase, macropain (proteasome)". Biochim. Biophys. Acta. 1037 (2): 178–85. doi:10.1016/0167-4838(90)90165-C. PMID 2306472.
• Kristensen P, Johnsen AH, Uerkvitz W, Tanaka K, Hendil KB (1995). "Human proteasome subunits from 2-dimensional gels identified by partial sequencing". Biochem. Biophys. Res. Commun. 205 (3): 1785–9. doi:10.1006/bbrc.1994.2876. PMID 7811265.
• Gerards WL, Hop FW, Hendriks IL, Bloemendal H (1994). "Cloning and expression of a human pro(tea)some beta-subunit cDNA: a homologue of the yeast PRE4-subunit essential for peptidylglutamyl-peptide hydrolase activity". FEBS Lett. 346 (2–3): 151–5. doi:10.1016/0014-5793(94)00454-4. PMID 8013624.
• Seeger M, Ferrell K, Frank R, Dubiel W (1997). "HIV-1 tat inhibits the 20 S proteasome and its 11 S regulator-mediated activation". J. Biol. Chem. 272 (13): 8145–8. doi:10.1074/jbc.272.13.8145. PMID 9079628.
• McCusker D, Jones T, Sheer D, Trowsdale J (1998). "Genetic relationships of the genes encoding the human proteasome beta subunits and the proteasome PA28 complex". Genomics. 45 (2): 362–7. doi:10.1006/geno.1997.4948. PMID 9344661.
• Rossi F, Evstafieva A, Pedrali-Noy G, Gallina A, Milanesi G (1997). "HsN3 proteasomal subunit as a target for human immunodeficiency virus type 1 Nef protein". Virology. 237 (1): 33–45. doi:10.1006/viro.1997.8752. PMID 9344905.
• Madani N, Kabat D (1998). "An endogenous inhibitor of human immunodeficiency virus in human lymphocytes is overcome by the viral Vif protein". J. Virol. 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 (1998). "Evidence for a newly discovered cellular anti-HIV-1 phenotype". Nat. Med. 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 (1999). "The complete primary structure of mouse 20S proteasomes". Immunogenetics. 49 (10): 835–42. doi:10.1007/s002510050562. PMID 10436176.
• Mulder LC, Muesing MA (2000). "Degradation of HIV-1 integrase by the N-end rule pathway". J. Biol. Chem. 275 (38): 29749–53. doi:10.1074/jbc.M004670200. PMID 10893419.
• Feng Y, Longo DL, Ferris DK (2001). "Polo-like kinase interacts with proteasomes and regulates their activity". Cell Growth Differ. 12 (1): 29–37. PMID 11205743.
• Lin Y, Martin J, Gruendler C, Farley J, Meng X, Li BY, Lechleider R, Huff C, Kim RH, Grasser WA, Paralkar V, Wang T (2002). "A novel link between the proteasome pathway and the signal transduction pathway of the bone morphogenetic proteins (BMPs)". BMC Cell Biol. 3: 15. doi:10.1186/1471-2121-3-15. PMC 117437. PMID 12097147.
• Sheehy AM, Gaddis NC, Choi JD, Malim MH (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 (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". J. Mol. Biol. 323 (4): 771–82. doi:10.1016/S0022-2836(02)00998-1. PMID 12419264.