PSMC5

PSMC5
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 2KRK, 3KW6
Identifiers
Aliases	PSMC5 , S8, SUG-1, SUG1, TBP10, TRIP1, p45, p45/SUG, proteasome 26S subunit, ATPase 5, RPT6
External IDs	OMIM: 601681 MGI: 105047 HomoloGene: 2098 GeneCards: PSMC5
Gene location (Human) Chr. Chromosome 17 (human) [1] Band 17q23.3 Start 63,827,152 bp [1] End 63,832,026 bp [1]
Gene location (Mouse) Chr. Chromosome 11 (mouse) [2] Band 11|11 E1 Start 106,146,980 bp [2] End 106,153,946 bp [2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in cerebellar cortex cerebellar hemisphere gastrocnemius muscle anterior pituitary gastric mucosa islet of Langerhans cingulate gyrus skin of abdomen prefrontal cortex Brodmann area 9 Top expressed in otic placode saccule medial vestibular nucleus dorsal tegmental nucleus pontine nuclei somite habenula lateral hypothalamus cerebellar cortex dorsomedial hypothalamic nucleus More reference expression data BioGPS More reference expression data
Gene ontology Molecular function nucleotide binding thyrotropin-releasing hormone receptor binding protein binding ATP binding signaling receptor binding hydrolase activity ATPase activity TBP-class protein binding transcription factor binding proteasome-activating activity Cellular component cytosol proteasome regulatory particle, base subcomplex blood microparticle membrane proteasome regulatory particle nucleoplasm inclusion body extracellular exosome cytoplasmic vesicle proteasome complex cytosolic proteasome complex cytoplasm proteasome accessory complex nucleus nuclear proteasome complex postsynapse Biological process positive regulation of RNA polymerase II transcription preinitiation complex assembly 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 positive regulation of inclusion body assembly MAPK cascade positive regulation of transcription, DNA-templated Fc-epsilon receptor signaling pathway protein catabolic process NIK/NF-kappaB signaling ubiquitin-dependent ERAD pathway negative regulation of programmed cell death anaphase-promoting complex-dependent catabolic process negative regulation of transcription, DNA-templated T cell receptor signaling pathway negative regulation of canonical Wnt signaling pathway proteasome-mediated ubiquitin-dependent protein catabolic process Wnt signaling pathway, planar cell polarity pathway positive regulation of proteasomal protein catabolic process 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 modulation of chemical synaptic transmission regulation of transcription by RNA polymerase II post-translational protein modification regulation of hematopoietic stem cell differentiation interleukin-1-mediated signaling pathway regulation of mitotic cell cycle phase transition Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 5705 19184 Ensembl ENSG00000087191 ENSMUSG00000020708 UniProt P62195 P62196 RefSeq (mRNA) NM_001199163 NM_002805 NM_008950 RefSeq (protein) NP_001186092 NP_002796 NP_032976 Location (UCSC) Chr 17: 63.83 – 63.83 Mb Chr 11: 106.15 – 106.15 Mb PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

26S protease regulatory subunit 8, also known as 26S proteasome AAA-ATPase subunit Rpt6, is an enzyme that in humans is encoded by the PSMC5 gene. ^{[5] [6] [7]} This protein is one of the 19 essential subunits of a complete assembled 19S proteasome complex ^[8] Six 26S proteasome AAA-ATPase subunits (Rpt1, Rpt2, Rpt3, Rpt4, Rpt5, and Rpt6 (this protein)) together with four non-ATPase subunits (Rpn1, Rpn2, Rpn10, and Rpn13) form the base sub complex of 19S regulatory particle for proteasome complex. ^[8]

Gene

The gene PSMC5 encodes one of the ATPase subunits, a member of the triple-A family of ATPases which have a chaperone-like activity. In addition to participation in proteasome functions, this subunit may participate in transcriptional regulation since it has been shown to interact with the thyroid hormone receptor and retinoid X receptor-alpha. ^[7] The human PSMC5 gene has 13 exons and locates at chromosome band 17q23.3.

Protein

The human protein 26S protease regulatory subunit 8 is 45.6kDa in size and composed of 406 amino acids. The calculated theoretical pI of this protein is 8.23. ^[9]

Complex assembly

26S proteasome complex is usually consisted of a 20S core particle (CP, or 20S proteasome) and one or two 19S regulatory particles (RP, or 19S proteasome) on either one side or both side of the barrel-shaped 20S. The CP and RPs pertain distinct structural characteristics and biological functions. In brief, 20S sub complex presents three types proteolytic activities, including caspase-like, trypsin-like, and chymotrypsin-like activities. These proteolytic active sites located in the inner side of a chamber formed by 4 stacked rings of 20S subunits, preventing random protein-enzyme encounter and uncontrolled protein degradation. The 19S regulatory particles can recognize ubiquitin-labeled protein as degradation substrate, unfold the protein to linear, open the gate of 20S core particle, and guide the substate into the proteolytic chamber. To meet such functional complexity, 19S regulatory particle contains at least 18 constitutive subunits. These subunits can be categorized into two classes based on the ATP dependence of subunits, ATP-dependent subunits and ATP-independent subunits. According to the protein interaction and topological characteristics of this multisubunit complex, the 19S regulatory particle is composed of a base and a lid subcomplex. The base consists of a ring of six AAA ATPases (Subunit Rpt1-6, systematic nomenclature) and four non-ATPase subunits (Rpn1, Rpn2, Rpn10, and Rpn13). Thus, 26S protease regulatory subunit 4 (Rpt2) is an essential component of forming the base subcomplex of 19S regulatory particle. For the assembly of 19S base sub complex, four sets of pivotal assembly chaperons (Hsm3/S5b, Nas2/P27, Nas6/P28, and Rpn14/PAAF1, nomenclature in yeast/mammals) were identified by four groups independently. ^{[10] [11] [12] [13] [14] [15]} These 19S regulatory particle base-dedicated chaperons all binds to individual ATPase subunits through the C-terminal regions. For example, Hsm3/S5b binds to the subunit Rpt1 and Rpt2 (this protein), Nas2/p27 to Rpt5, Nas6/p28 to Rpt3, and Rpn14/PAAAF1 to Rpt6 (this protein), respectively. Subsequently, three intermediate assembly modules are formed as following, the Nas6/p28-Rpt3-Rpt6-Rpn14/PAAF1 module, the Nas2/p27-Rpt4-Rpt5 module, and the Hsm3/S5b-Rpt1-Rpt2-Rpn2 module. Eventually, these three modules assemble together to form the heterohexameric ring of 6 Atlases with Rpn1. The final addition of Rpn13 indicates the completion of 19S base sub complex assembly. ^[8]

Function

As the degradation machinery that is responsible for ~70% of intracellular proteolysis, ^[16] proteasome complex (26S proteasome) plays a critical roles in maintaining the homeostasis of cellular proteome. Accordingly, misfolded proteins and damaged protein need to be continuously removed to recycle amino acids for new synthesis; in parallel, some key regulatory proteins fulfill their biological functions via selective degradation; furthermore, proteins are digested into peptides for MHC class I antigen presentation. To meet such complicated demands in biological process via spatial and temporal proteolysis, protein substrates have to be recognized, recruited, and eventually hydrolyzed in a well controlled fashion. Thus, 19S regulatory particle pertains a series of important capabilities to address these functional challenges. To recognize protein as designated substrate, 19S complex has subunits that are capable to recognize proteins with a special degradative tag, the ubiquitinylation. It also have subunits that can bind with nucleotides (e.g., ATPs) in order to facilitate the association between 19S and 20S particles, as well as to cause confirmation changes of alpha subunit C-terminals that form the substate entrance of 20S complex.

The ATPases subunits assemble into a six-membered ring with a sequence of Rpt1–Rpt5–Rpt4–Rpt3–Rpt6–Rpt2, which interacts with the seven-membered alpha ring of 20S core particle and establishes an asymmetric interface between the 19S RP and the 20S CP. ^{[17] [18]} Three C-terminal tails with HbYX motifs of distinct Rpt ATPases insert into pockets between two defined alpha subunits of the CP and regulate the gate opening of the central channels in the CP alpha ring. ^{[19] [20]} Evidence showed that ATPase subunit Rpt5, along with other ubuiqintinated 19S proteasome subunits (Rpn13, Rpn10) and the deubiquitinating enzyme Uch37, can be ubiquitinated in situ by proteasome-associating ubiquitination enzymes. Ubiquitination of proteasome subunits can regulates proteasomal activity in response to the alteration of cellular ubiquitination levels. ^[21]

Interactions

PSMC5 has been shown to interact with:

• PSMC3, ^[22]
• PSMC4, ^{[23] [24]}
• Sp1 transcription factor, ^{[25] [26]} and
• XPB. ^[27]

Children with PSMC5 Mutations

As of 2021, only 18 reports of children with PSMC5 mutations have been discovered. <GeneMatcher> There is one foundation that is performing research with children who has PSMC5 mutations called PSMC5 Foundation, www.psmc5.org. The aim is to find therapies and learn more about how to resolve issues with mutations. The common effects have been developmental delays, ranging from motor delays to minimal expressive language.

References

1. GRCh38: Ensembl release 89: ENSG00000087191 - Ensembl, May 2017
2. GRCm38: Ensembl release 89: ENSMUSG00000020708 - Ensembl, May 2017
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6. Hoyle J, Tan KH, Fisher EM (March 1997). "Localization of genes encoding two human one-domain members of the AAA family: PSMC5 (the thyroid hormone receptor-interacting protein, TRIP1) and PSMC3 (the Tat-binding protein, TBP1)". Hum Genet. 99 (2): 285–8. doi:10.1007/s004390050356. PMID   9048938. S2CID   29818936.
7. "Entrez Gene: PSMC5 proteasome (prosome, macropain) 26S subunit, ATPase, 5".
8. Gu ZC, Enenkel C (Dec 2014). "Proteasome assembly". Cellular and Molecular Life Sciences. 71 (24): 4729–45. doi:10.1007/s00018-014-1699-8. PMID   25107634. S2CID   15661805.
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10. Le Tallec B, Barrault MB, Guérois R, Carré T, Peyroche A (Feb 2009). "Hsm3/S5b participates in the assembly pathway of the 19S regulatory particle of the proteasome". Molecular Cell. 33 (3): 389–99. doi: 10.1016/j.molcel.2009.01.010 . PMID   19217412.
11. Funakoshi M, Tomko RJ, Kobayashi H, Hochstrasser M (May 2009). "Multiple assembly chaperones govern biogenesis of the proteasome regulatory particle base". Cell. 137 (5): 887–99. doi:10.1016/j.cell.2009.04.061. PMC   2718848 . PMID   19446322.
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14. Saeki Y, Toh-E A, Kudo T, Kawamura H, Tanaka K (May 2009). "Multiple proteasome-interacting proteins assist the assembly of the yeast 19S regulatory particle". Cell. 137 (5): 900–13. doi: 10.1016/j.cell.2009.05.005 . PMID   19446323. S2CID   14151131.
15. Kaneko T, Hamazaki J, Iemura S, Sasaki K, Furuyama K, Natsume T, Tanaka K, Murata S (May 2009). "Assembly pathway of the Mammalian proteasome base subcomplex is mediated by multiple specific chaperones". Cell. 137 (5): 914–25. doi: 10.1016/j.cell.2009.05.008 . PMID   19490896. S2CID   18551885.
16. Rock KL, Gramm C, Rothstein L, Clark K, Stein R, Dick L, Hwang D, Goldberg AL (Sep 1994). "Inhibitors of the proteasome block the degradation of most cell proteins and the generation of peptides presented on MHC class I molecules". Cell. 78 (5): 761–71. doi:10.1016/s0092-8674(94)90462-6. PMID   8087844. S2CID   22262916.
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21. Jacobson AD, MacFadden A, Wu Z, Peng J, Liu CW (Jun 2014). "Autoregulation of the 26S proteasome by in situ ubiquitination". Molecular Biology of the Cell. 25 (12): 1824–35. doi:10.1091/mbc.E13-10-0585. PMC   4055262 . PMID   24743594.
22. Ishizuka T, Satoh T, Monden T, Shibusawa N, Hashida T, Yamada M, Mori M (August 2001). "Human immunodeficiency virus type 1 Tat binding protein-1 is a transcriptional coactivator specific for TR". Mol. Endocrinol. 15 (8): 1329–43. doi: 10.1210/mend.15.8.0680 . PMID   11463857.
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24. Ewing RM, Chu P, Elisma F, Li H, Taylor P, Climie S, McBroom-Cerajewski L, Robinson MD, O'Connor L, Li M, Taylor R, Dharsee M, Ho Y, Heilbut A, Moore L, Zhang S, Ornatsky O, Bukhman YV, Ethier M, Sheng Y, Vasilescu J, Abu-Farha M, Lambert JP, Duewel HS, Stewart II, Kuehl B, Hogue K, Colwill K, Gladwish K, Muskat B, Kinach R, Adams SL, Moran MF, Morin GB, Topaloglou T, Figeys D (2007). "Large-scale mapping of human protein-protein interactions by mass spectrometry". Mol. Syst. Biol. 3: 89. doi:10.1038/msb4100134. PMC   1847948 . PMID   17353931.
25. Su K, Yang X, Roos MD, Paterson AJ, Kudlow JE (June 2000). "Human Sug1/p45 is involved in the proteasome-dependent degradation of Sp1". Biochem. J. 348. 348 Pt 2 (2): 281–9. doi:10.1042/0264-6021:3480281. PMC   1221064 . PMID   10816420.
26. Wang YT, Chuang JY, Shen MR, Yang WB, Chang WC, Hung JJ (July 2008). "Sumoylation of specificity protein 1 augments its degradation by changing the localization and increasing the specificity protein 1 proteolytic process". J. Mol. Biol. 380 (5): 869–85. doi:10.1016/j.jmb.2008.05.043. PMID   18572193.
27. Weeda G, Rossignol M, Fraser RA, Winkler GS, Vermeulen W, van 't Veer LJ, Ma L, Hoeijmakers JH, Egly JM (June 1997). "The XPB subunit of repair/transcription factor TFIIH directly interacts with SUG1, a subunit of the 26S proteasome and putative transcription factor". Nucleic Acids Res. 25 (12): 2274–83. doi:10.1093/nar/25.12.2274. PMC   146752 . PMID   9173976.

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. S2CID   16340355.
• Nelbock P, Dillon PJ, Perkins A, Rosen CA (1990). "A cDNA for a protein that interacts with the human immunodeficiency virus Tat transactivator". Science. 248 (4963): 1650–3. Bibcode:1990Sci...248.1650N. doi:10.1126/science.2194290. PMID   2194290.
• Akiyama K, Yokota K, Kagawa S, Shimbara N, DeMartino GN, Slaughter CA, Noda C, Tanaka K (1995). "cDNA cloning of a new putative ATPase subunit p45 of the human 26S proteasome, a homolog of yeast transcriptional factor Sug1p". FEBS Lett. 363 (1–2): 151–6. doi: 10.1016/0014-5793(95)00304-R . PMID   7729537. S2CID   638369.
• Lee JW, Choi HS, Gyuris J, Brent R, Moore DD (1995). "Two classes of proteins dependent on either the presence or absence of thyroid hormone for interaction with the thyroid hormone receptor". Mol. Endocrinol. 9 (2): 243–54. doi: 10.1210/mend.9.2.7776974 . PMID   7776974.
• Lee JW, Ryan F, Swaffield JC, Johnston SA, Moore DD (1995). "Interaction of thyroid-hormone receptor with a conserved transcriptional mediator". Nature. 374 (6517): 91–4. Bibcode:1995Natur.374...91L. doi:10.1038/374091a0. PMID   7870181. S2CID   4324595.
• Shaw DR, Ennis HL (1993). "Molecular cloning and developmental regulation of Dictyostelium discoideum homologues of the human and yeast HIV1 Tat-binding protein". Biochem. Biophys. Res. Commun. 193 (3): 1291–6. doi:10.1006/bbrc.1993.1765. PMID   8323548.
• Ohana B, Moore PA, Ruben SM, Southgate CD, Green MR, Rosen CA (1993). "The type 1 human immunodeficiency virus Tat binding protein is a transcriptional activator belonging to an additional family of evolutionarily conserved genes". Proc. Natl. Acad. Sci. U.S.A. 90 (1): 138–42. Bibcode:1993PNAS...90..138O. doi: 10.1073/pnas.90.1.138 . PMC   45615 . PMID   8419915.
• Dubiel W, Ferrell K, Rechsteiner M (1993). "Peptide sequencing identifies MSS1, a modulator of HIV Tat-mediated transactivation, as subunit 7 of the 26 S protease". FEBS Lett. 323 (3): 276–8. doi:10.1016/0014-5793(93)81356-5. PMID   8500623. S2CID   26726988.
• vom Baur E, Zechel C, Heery D, Heine MJ, Garnier JM, Vivat V, Le Douarin B, Gronemeyer H, Chambon P, Losson R (1996). "Differential ligand-dependent interactions between the AF-2 activating domain of nuclear receptors and the putative transcriptional intermediary factors mSUG1 and TIF1". EMBO J. 15 (1): 110–24. doi:10.1002/j.1460-2075.1996.tb00339.x. PMC   449923 . PMID   8598193.
• Andersson B, Wentland MA, Ricafrente JY, Liu W, Gibbs RA (1996). "A "double adaptor" method for improved shotgun library construction". Anal. Biochem. 236 (1): 107–13. doi:10.1006/abio.1996.0138. PMID   8619474.
• Wang W, Chevray PM, Nathans D (1996). "Mammalian Sug1 and c-Fos in the nuclear 26S proteasome". Proc. Natl. Acad. Sci. U.S.A. 93 (16): 8236–40. Bibcode:1996PNAS...93.8236W. doi: 10.1073/pnas.93.16.8236 . PMC   38653 . PMID   8710853.
• 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.
• Yu W, Andersson B, Worley KC, Muzny DM, Ding Y, Liu W, Ricafrente JY, Wentland MA, Lennon G, Gibbs RA (1997). "Large-scale concatenation cDNA sequencing". Genome Res. 7 (4): 353–8. doi:10.1101/gr.7.4.353. PMC   139146 . PMID   9110174.
• Weeda G, Rossignol M, Fraser RA, Winkler GS, Vermeulen W, van 't Veer LJ, Ma L, Hoeijmakers JH, Egly JM (1997). "The XPB subunit of repair/transcription factor TFIIH directly interacts with SUG1, a subunit of the 26S proteasome and putative transcription factor". Nucleic Acids Res. 25 (12): 2274–83. doi:10.1093/nar/25.12.2274. PMC   146752 . PMID   9173976.
• Chen Y, Sharp ZD, Lee WH (1997). "HEC binds to the seventh regulatory subunit of the 26 S proteasome and modulates the proteolysis of mitotic cyclins". J. Biol. Chem. 272 (38): 24081–7. doi: 10.1074/jbc.272.38.24081 . PMID   9295362.
• Tipler CP, Hutchon SP, Hendil K, Tanaka K, Fishel S, Mayer RJ (1998). "Purification and characterization of 26S proteasomes from human and mouse spermatozoa". Mol. Hum. Reprod. 3 (12): 1053–60. doi:10.1093/molehr/3.12.1053. PMID   9464850.