PSMC3

26S protease regulatory subunit 6A, also known as 26S proteasome AAA-ATPase subunit Rpt5, is an enzyme that in humans is encoded by the PSMC3 gene.[5][6] This protein is one of the 19 essential subunits of a complete assembled 19S proteasome complex[7] Six 26S proteasome AAA-ATPase subunits (Rpt1, Rpt2, Rpt3, Rpt4, Rpt5 (this protein), and Rpt6) together with four non-ATPase subunits (Rpn1, Rpn2, Rpn10, and Rpn13) form the base sub complex of 19S regulatory particle for proteasome complex.[7]

PSMC3
Identifiers
Aliases	PSMC3, TBP1, proteasome 26S subunit, ATPase 3
External IDs	OMIM: 186852 MGI: 1098754 HomoloGene: 2097 GeneCards: PSMC3
Gene location (Human) Chr. Chromosome 11 (human)[1] Band 11p11.2 Start 47,418,769 bp[1] End 47,426,473 bp[1]
Gene location (Mouse) Chr. Chromosome 2 (mouse)[2] Band 2 E1|2 50.44 cM Start 91,054,009 bp[2] End 91,066,369 bp[2]
RNA expression pattern More reference expression data
Gene ontology Molecular function • nucleotide binding • ATPase activity • hydrolase activity • TBP-class protein binding • ATP binding • GO:0001948 protein binding • identical protein binding • proteasome-activating ATPase activity Cellular component • nucleoplasm • cytoplasm • proteasome regulatory particle, base subcomplex • cytosol • cytosolic proteasome complex • membrane • P-body • proteasome accessory complex • nuclear proteasome complex • proteasome complex • extracellular region • secretory granule lumen • ficolin-1-rich granule lumen • cell nucleus Biological process • NIK/NF-kappaB signaling • MAPK cascade • regulation of mRNA stability • protein polyubiquitination • Fc-epsilon receptor signaling pathway • regulation of cellular amino acid metabolic process • protein catabolic process • antigen processing and presentation of exogenous peptide antigen via MHC class I, TAP-dependent • tumor necrosis factor-mediated signaling pathway • blastocyst development • stimulatory C-type lectin receptor signaling pathway • ubiquitin-dependent ERAD pathway • anaphase-promoting complex-dependent catabolic process • negative regulation of canonical Wnt signaling pathway • positive regulation of RNA polymerase II transcriptional preinitiation complex assembly • T cell receptor signaling pathway • positive regulation of canonical Wnt signaling pathway • positive regulation of proteasomal protein catabolic process • GO:0022415 viral process • Wnt signaling pathway, planar cell polarity pathway • proteasome-mediated ubiquitin-dependent protein catabolic process • negative regulation of G2/M transition of mitotic cell cycle • protein deubiquitination • SCF-dependent proteasomal ubiquitin-dependent protein catabolic process • neutrophil degranulation • transmembrane transport • regulation of transcription from RNA polymerase II promoter in response to hypoxia • modulation by host of viral transcription • positive regulation of transcription from RNA polymerase II promoter • post-translational 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	5702	19182
Ensembl	ENSG00000165916	ENSMUSG00000002102
UniProt	P17980	O88685
RefSeq (mRNA)	NM_002804	NM_008948
RefSeq (protein)	NP_002795	NP_032974
Location (UCSC)	Chr 11: 47.42 – 47.43 Mb	Chr 2: 91.05 – 91.07 Mb
PubMed search	[3]	[4]
Wikidata
View/Edit Human View/Edit Mouse

Gene

The gene PSMC3 encodes one of the ATPase subunits, a member of the triple-A family of ATPases that have chaperone-like activity. This subunit may compete with PSMC2 for binding to the HIV tat protein to regulate the interaction between the viral protein and the transcription complex. A pseudogene has been identified on chromosome 9.[8] The human PSMC3 gene has 12 exons and locates at chromosome band 11p11.2.

Protein

The human protein 26S protease regulatory subunit 6A is 49kDa in size and composed of 439 amino acids. The calculated theoretical pI of this protein is 5.68.[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 (this protein), Nas6/p28 to Rpt3, and Rpn14/PAAAF1 to Rpt6, 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.[7]

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 eastablishs 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

PSMC3 has been shown to interact with PSMC5[22] and Von Hippel-Lindau tumor suppressor.[23]

References

1. GRCh38: Ensembl release 89: ENSG00000165916 - Ensembl, May 2017
2. GRCm38: Ensembl release 89: ENSMUSG00000002102 - Ensembl, May 2017
3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
5. Hoyle J, Tan KH, Fisher EM (Mar 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.
6. Tanahashi N, Suzuki M, Fujiwara T, Takahashi E, Shimbara N, Chung CH, Tanaka K (Mar 1998). "Chromosomal localization and immunological analysis of a family of human 26S proteasomal ATPases". Biochem Biophys Res Commun. 243 (1): 229–32. doi:10.1006/bbrc.1997.7892. PMID 9473509.
7. 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.
8. "Entrez Gene: PSMC3 proteasome (prosome, macropain) 26S subunit, ATPase, 3".
9. "Uniprot: P17980 - PRS6A_HUMAN".
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.
12. Park S, Roelofs J, Kim W, Robert J, Schmidt M, Gygi SP, Finley D (Jun 2009). "Hexameric assembly of the proteasomal ATPases is templated through their C termini". Nature. 459 (7248): 866–70. Bibcode:2009Natur.459..866P. doi:10.1038/nature08065. PMC 2722381. PMID 19412160.
13. Roelofs J, Park S, Haas W, Tian G, McAllister FE, Huo Y, Lee BH, Zhang F, Shi Y, Gygi SP, Finley D (Jun 2009). "Chaperone-mediated pathway of proteasome regulatory particle assembly". Nature. 459 (7248): 861–5. Bibcode:2009Natur.459..861R. doi:10.1038/nature08063. PMC 2727592. PMID 19412159.
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.
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.
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.
17. Tian G, Park S, Lee MJ, Huck B, McAllister F, Hill CP, Gygi SP, Finley D (Nov 2011). "An asymmetric interface between the regulatory and core particles of the proteasome". Nature Structural & Molecular Biology. 18 (11): 1259–67. doi:10.1038/nsmb.2147. PMC 3210322. PMID 22037170.
18. Lander GC, Estrin E, Matyskiela ME, Bashore C, Nogales E, Martin A (Feb 2012). "Complete subunit architecture of the proteasome regulatory particle". Nature. 482 (7384): 186–91. Bibcode:2012Natur.482..186L. doi:10.1038/nature10774. PMC 3285539. PMID 22237024.
19. Gillette TG, Kumar B, Thompson D, Slaughter CA, DeMartino GN (Nov 2008). "Differential roles of the COOH termini of AAA subunits of PA700 (19 S regulator) in asymmetric assembly and activation of the 26 S proteasome". The Journal of Biological Chemistry. 283 (46): 31813–31822. doi:10.1074/jbc.M805935200. PMC 2581596. PMID 18796432.
20. Smith DM, Chang SC, Park S, Finley D, Cheng Y, Goldberg AL (Sep 2007). "Docking of the proteasomal ATPases' carboxyl termini in the 20S proteasome's alpha ring opens the gate for substrate entry". Molecular Cell. 27 (5): 731–744. doi:10.1016/j.molcel.2007.06.033. PMC 2083707. PMID 17803938.
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 (Aug 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.
23. Corn PG, McDonald ER, Herman JG, El-Deiry WS (Nov 2003). "Tat-binding protein-1, a component of the 26S proteasome, contributes to the E3 ubiquitin ligase function of the von Hippel-Lindau protein". Nat. Genet. 35 (3): 229–37. doi:10.1038/ng1254. PMID 14556007.

Further reading

• Coux O, Tanaka K, Goldberg AL (1996). "Structure and functions of the 20S and 26S proteasomes". Annu. Rev. Biochem. 65: 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.
• 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.
• Maruyama K, Sugano S (1994). "Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides". Gene. 138 (1–2): 171–4. doi:10.1016/0378-1119(94)90802-8. PMID 8125298.
• 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.
• DeMartino GN, Proske RJ, Moomaw CR, Strong AA, Song X, Hisamatsu H, Tanaka K, Slaughter CA (1996). "Identification, purification, and characterization of a PA700-dependent activator of the proteasome". J. Biol. Chem. 271 (6): 3112–8. doi:10.1074/jbc.271.6.3112. PMID 8621709.
• 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.
• Tanaka T, Nakamura T, Takagi H, Sato M (1997). "Molecular cloning and characterization of a novel TBP-1 interacting protein (TBPIP):enhancement of TBP-1 action on Tat by TBPIP". Biochem. Biophys. Res. Commun. 239 (1): 176–81. doi:10.1006/bbrc.1997.7447. PMID 9345291.
• Suzuki Y, Yoshitomo-Nakagawa K, Maruyama K, Suyama A, Sugano S (1997). "Construction and characterization of a full length-enriched and a 5'-end-enriched cDNA library". Gene. 200 (1–2): 149–56. doi:10.1016/S0378-1119(97)00411-3. PMID 9373149.
• Nakamura T, Tanaka T, Takagi H, Sato M (1998). "Cloning and heterogeneous in vivo expression of Tat binding protein-1 (TBP-1) in the mouse". Biochim. Biophys. Acta. 1399 (1): 93–100. doi:10.1016/s0167-4781(98)00105-5. PMID 9714759.
• 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. 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.
• Park BW, O'Rourke DM, Wang Q, Davis JG, Post A, Qian X, Greene MI (1999). "Induction of the Tat-binding protein 1 gene accompanies the disabling of oncogenic erbB receptor tyrosine kinases". Proc. Natl. Acad. Sci. U.S.A. 96 (11): 6434–8. Bibcode:1999PNAS...96.6434P. doi:10.1073/pnas.96.11.6434. PMC 26899. PMID 10339605.
• Tanahashi N, Murakami Y, Minami Y, Shimbara N, Hendil KB, Tanaka K (2000). "Hybrid proteasomes. Induction by interferon-gamma and contribution to ATP-dependent proteolysis". J. Biol. Chem. 275 (19): 14336–45. doi:10.1074/jbc.275.19.14336. PMID 10799514.
• Ijichi H, Tanaka T, Nakamura T, Yagi H, Hakuba A, Sato M (2000). "Molecular cloning and characterization of a human homologue of TBPIP, a BRCA1 locus-related gene". Gene. 248 (1–2): 99–107. doi:10.1016/S0378-1119(00)00141-4. PMID 10806355.