PSMB4
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| Location (UCSC) | Chr 1: 151.4 – 151.4 Mb | Chr 3: 94.79 – 94.79 Mb | |||||||
| PubMed search | [3] | [4] | |||||||
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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.[5]
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.[6] 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.[7][8]
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.[8] 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.[9][10] 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.[10][11]
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
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
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
Interactions
PSMB4 has been shown to interact with Mothers against decapentaplegic homolog 1.[33][34]
References
- ^ a b c GRCh38: Ensembl release 89: ENSG00000159377 – Ensembl, May 2017
- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000005779 – Ensembl, May 2017
- ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- PMID 7918633.
- ^ "Entrez Gene: PSMB4 proteasome (prosome, macropain) subunit, beta type, 4".
- PMID 8811196.
- ^ PMID 23495936.
- S2CID 4261663.
- ^ S2CID 27481109.
- PMID 16857963.
- PMID 24457024.
- PMID 9383453.
- S2CID 14103185.
- PMID 25324717.
- PMID 24380730.
- PMID 25133688.
- PMID 25651176.
- ^ PMID 10723801.
- PMID 25560147.
- PMID 10899438.
- S2CID 2211658.
- ^ S2CID 22396490.
- S2CID 5780576.
- PMID 12792671.
- PMID 23220331.
- PMID 20159828.
- S2CID 7073263.
- PMID 12654543.
- S2CID 26973319.
- PMID 12375310.
- PMID 25157275.
- PMID 12097147.
- 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. PMID 8811196.
- Goff SP (2003). "Death by deamination: a novel host restriction system for HIV-1". Cell. 114 (3): 281–3. S2CID 16340355.
- 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. S2CID 41855774.
- 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. 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. 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. 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. 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. 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. 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. 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. S2CID 25235070.
- 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. S2CID 20977116.
- Mulder LC, Muesing MA (2000). "Degradation of HIV-1 integrase by the N-end rule pathway". J. Biol. Chem. 275 (38): 29749–53. 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. 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. S2CID 4403228.
- 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. PMID 12419264.
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