PSMC6

PSMC6
Identifiers
Aliases	PSMC6 , CADP44, HEL-S-73, P44, SUG2, p42, proteasome 26S subunit, ATPase 6, RPT5
External IDs	OMIM: 602708; MGI: 1914339; HomoloGene: 100630; GeneCards: PSMC6; OMA:PSMC6 - orthologs
Gene location (Human) Chr. Chromosome 14 (human) [1] Band 14q22.1 Start 52,707,178 bp [1] End 52,728,590 bp [1]
Gene location (Mouse) Chr. Chromosome 14 (mouse) [2] Band 14|14 C1 Start 45,567,245 bp [2] End 45,587,162 bp [2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in palpebral conjunctiva amniotic fluid tibia germinal epithelium visceral pleura parietal pleura oral cavity endometrium gastrocnemius muscle Achilles tendon Top expressed in atrioventricular valve maxillary prominence abdominal wall otic placode olfactory epithelium extensor digitorum longus muscle plantaris muscle medial ganglionic eminence hand saccule More reference expression data BioGPS More reference expression data
Gene ontology Molecular function nucleotide binding protein-macromolecule adaptor activity ATPase activity protein binding TBP-class protein binding ATP binding hydrolase activity identical protein binding proteasome-activating activity Cellular component cytoplasm nuclear proteasome complex cytosol proteasome regulatory particle, base subcomplex membrane proteasome accessory complex nucleoplasm cytosolic proteasome complex proteasome complex extracellular exosome nucleus 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 ubiquitin-dependent protein catabolic process 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 Fc-epsilon receptor signaling pathway protein catabolic process NIK/NF-kappaB signaling ubiquitin-dependent ERAD pathway anaphase-promoting complex-dependent catabolic process T cell receptor signaling pathway negative regulation of canonical Wnt signaling pathway positive regulation of proteasomal protein catabolic 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 transmembrane transport regulation of transcription from RNA polymerase II promoter in response to hypoxia 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 5706 67089 Ensembl ENSG00000100519 ENSMUSG00000021832 UniProt P62333 P62334 RefSeq (mRNA) NM_002806 NM_001366414 NM_025959 RefSeq (protein) NP_002797 NP_001353343 NP_080235 Location (UCSC) Chr 14: 52.71 – 52.73 Mb Chr 14: 45.57 – 45.59 Mb PubMed search [3] [4]
Wikidata
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26S protease regulatory subunit S10B, also known as 26S proteasome AAA-ATPase subunit Rpt4, is an enzyme that in humans is encoded by the PSMC6 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 (this protein), Rpt5, 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. ^[8]

Gene

The gene PSMC6 encodes one of the ATPase subunits, a member of the triple-A family of ATPases which have a chaperone-like activity. Pseudogenes have been identified on chromosomes 8 and 12. ^[7] The human gene PSMC6 has 15 exons and locates at chromosome band 14q22.1.

Protein

The human protein 26S protease regulatory subunit S10B is 44kDa in size and composed of 389 amino acids. The calculated theoretical pI of this protein is 7.09. ^[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 substrate 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, 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 substrate 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]

References

1. GRCh38: Ensembl release 89: ENSG00000100519 – Ensembl, May 2017
2. GRCm38: Ensembl release 89: ENSMUSG00000021832 – 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. Fujiwara T, Watanabe TK, Tanaka K, Slaughter CA, DeMartino GN (Jun 1996). "cDNA cloning of p42, a shared subunit of two proteasome regulatory proteins, reveals a novel member of the AAA protein family". FEBS Letters. 387 (2–3): 184–8. Bibcode:1996FEBSL.387..184F. doi: 10.1016/0014-5793(96)00489-9 . PMID   8674546.
6. Tanahashi N, Suzuki M, Fujiwara T, Takahashi E, Shimbara N, Chung CH, Tanaka K (Feb 1998). "Chromosomal localization and immunological analysis of a family of human 26S proteasomal ATPases". Biochemical and Biophysical Research Communications. 243 (1): 229–32. doi:10.1006/bbrc.1997.7892. PMID   9473509.
7. "Entrez Gene: PSMC6 proteasome (prosome, macropain) 26S subunit, ATPase, 6".
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. PMC   11113775 . PMID   25107634. S2CID   15661805.
9. "Uniprot: P62333 - PRS10_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. S2CID   22262916.
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.

Further reading

• 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.
• Hastings R, Walker G, Eyheralde I, Dawson S, Billett M, Mayer RJ (Apr 1999). "Activator complexes containing the proteasomal regulatory ATPases S10b (SUG2) and S6 (TBP1) in different tissues and organisms". Molecular Biology Reports. 26 (1–2): 35–8. doi:10.1023/A:1006903903534. PMID   10363644. S2CID   25213803.
• Goff SP (Aug 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.
• DeMartino GN, Proske RJ, Moomaw CR, Strong AA, Song X, Hisamatsu H, Tanaka K, Slaughter CA (Feb 1996). "Identification, purification, and characterization of a PA700-dependent activator of the proteasome". The Journal of Biological Chemistry. 271 (6): 3112–8. doi: 10.1074/jbc.271.6.3112 . PMID   8621709.
• Seeger M, Ferrell K, Frank R, Dubiel W (Mar 1997). "HIV-1 tat inhibits the 20 S proteasome and its 11 S regulator-mediated activation". The Journal of Biological Chemistry. 272 (13): 8145–8. doi: 10.1074/jbc.272.13.8145 . PMID   9079628.
• Tipler CP, Hutchon SP, Hendil K, Tanaka K, Fishel S, Mayer RJ (Dec 1997). "Purification and characterization of 26S proteasomes from human and mouse spermatozoa". Molecular Human Reproduction. 3 (12): 1053–60. doi:10.1093/molehr/3.12.1053. PMID   9464850.
• Madani N, Kabat D (Dec 1998). "An endogenous inhibitor of human immunodeficiency virus in human lymphocytes is overcome by the viral Vif protein". Journal of Virology. 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 (Dec 1998). "Evidence for a newly discovered cellular anti-HIV-1 phenotype". Nature Medicine. 4 (12): 1397–400. doi:10.1038/3987. PMID   9846577. S2CID   25235070.
• Russell SJ, Steger KA, Johnston SA (Jul 1999). "Subcellular localization, stoichiometry, and protein levels of 26 S proteasome subunits in yeast". The Journal of Biological Chemistry. 274 (31): 21943–52. doi: 10.1074/jbc.274.31.21943 . PMID   10419517.
• Mulder LC, Muesing MA (Sep 2000). "Degradation of HIV-1 integrase by the N-end rule pathway". The Journal of Biological Chemistry. 275 (38): 29749–53. doi: 10.1074/jbc.M004670200 . PMID   10893419.
• Russell SJ, Gonzalez F, Joshua-Tor L, Johnston SA (Oct 2001). "Selective chemical inactivation of AAA proteins reveals distinct functions of proteasomal ATPases". Chemistry & Biology. 8 (10): 941–50. doi: 10.1016/S1074-5521(01)00060-6 . PMID   11590019.
• Sheehy AM, Gaddis NC, Choi JD, Malim MH (Aug 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. S2CID   4403228.
• Huang X, Seifert U, Salzmann U, Henklein P, Preissner R, Henke W, Sijts AJ, Kloetzel PM, Dubiel W (Nov 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". Journal of Molecular Biology. 323 (4): 771–82. doi:10.1016/S0022-2836(02)00998-1. PMID   12419264.
• Reiser G, Bernstein HG (Dec 2002). "Neurons and plaques of Alzheimer's disease patients highly express the neuronal membrane docking protein p42IP4/centaurin alpha". NeuroReport. 13 (18): 2417–9. doi:10.1097/00001756-200212200-00008. PMID   12499840. S2CID   24499944.
• Gaddis NC, Chertova E, Sheehy AM, Henderson LE, Malim MH (May 2003). "Comprehensive investigation of the molecular defect in vif-deficient human immunodeficiency virus type 1 virions". Journal of Virology. 77 (10): 5810–20. doi:10.1128/JVI.77.10.5810-5820.2003. PMC   154025 . PMID   12719574.