Biology:PSMD10

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Short description: Enzyme found in humans


A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example

26S proteasome non-ATPase regulatory subunit 10 or gankyrin is an enzyme that in humans is encoded by the PSMD10 gene.[1] First isolated in 1998 by Tanaka et al.; Gankyrin is an oncoprotein that is a component of the 19S regulatory cap of the proteasome.[2][3] Structurally, it contains a 33-amino acid ankyrin repeat that forms a series of alpha helices.[4] It plays a key role in regulating the cell cycle via protein-protein interactions with the cyclin-dependent kinase CDK4. It also binds closely to the E3 ubiquitin ligase MDM2, which is a regulator of the degradation of p53 and retinoblastoma protein, both transcription factors involved in tumor suppression and found mutated in many cancers.[5] Gankyrin also has an anti-apoptotic effect and is overexpressed in certain types of tumor cells such as hepatocellular carcinoma.[6]

Function

The 26S proteasome is a multicatalytic proteinase complex with a highly ordered structure composed of 2 complexes, a 20S core and a 19S regulator. The 20S core is composed of 4 rings of 28 non-identical subunits; 2 rings are composed of 7 alpha subunits and 2 rings are composed of 7 beta subunits. The 19S regulator is composed of a base, which contains 6 ATPase subunits and 2 non-ATPase subunits, and a lid, which contains up to 10 non-ATPase subunits. Proteasomes are distributed throughout eukaryotic cells at a high concentration and cleave peptides in an ATP/ubiquitin-dependent process in a non-lysosomal pathway. An essential function of a modified proteasome, the immunoproteasome, is the processing of class I MHC peptides. This gene encodes a non-ATPase subunit of the 19S regulator. Two transcripts encoding different isoforms have been described. Pseudogenes have been identified on chromosomes 3 and 20.[7]

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. More recently, more effort has 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) [8] 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.[9] 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,[10][11] cardiovascular diseases,[12][13][14] inflammatory responses and autoimmune diseases,[15] and systemic DNA damage responses leading to malignancies.[16]

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,[17] Parkinson's disease[18] and Pick's disease,[19] Amyotrophic lateral sclerosis (ALS),[19] Huntington's disease,[18] Creutzfeldt–Jakob disease,[20] and motor neuron diseases, polyglutamine (PolyQ) diseases, Muscular dystrophies[21] and several rare forms of neurodegenerative diseases associated with dementia.[22] As part of the ubiquitin–proteasome system (UPS), the proteasome maintains cardiac protein homeostasis and thus plays a significant role in cardiac ischemic injury,[23] ventricular hypertrophy[24] and heart failure.[25] 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.[26] 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).[15] 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.[27] Lastly, autoimmune disease patients with SLE, Sjögren syndrome and rheumatoid arthritis (RA) predominantly exhibit circulating proteasomes which can be applied as clinical biomarkers.[28]

Interactions

PSMD10 has been shown to interact with:

References

  1. ↑ "cDNA cloning and functional analysis of p28 (Nas6p) and p40.5 (Nas7p), two novel regulatory subunits of the 26S proteasome". Gene 216 (1): 113–22. Aug 1998. doi:10.1016/S0378-1119(98)00309-6. PMID 9714768. 
  2. ↑ Lozano, Guillermina; Zambetti, Gerard P. (2005-07-01). "Gankyrin: An intriguing name for a novel regulator of p53 and RB". Cancer Cell 8 (1): 3–4. doi:10.1016/j.ccr.2005.06.014. ISSN 1535-6108. PMID 16023592. 
  3. ↑ Hori, Tomoko; Kato, Seishi; Saeki, Mihoro; DeMartino, George N.; Slaughter, Clive A.; Takeuchi, Junko; Toh-e, Akio; Tanaka, Keiji (1998-08-17). "cDNA cloning and functional analysis of p28 (Nas6p) and p40.5 (Nas7p), two novel regulatory subunits of the 26S proteasome1The nucleotide sequence data reported in this paper will appear in the GSDB, DDBJ, EMBL and NCBI Nucleotide Sequence Databases with the following accession numbers: p28 (AB009619) and p40.5 (AB009398).1" (in en). Gene 216 (1): 113–122. doi:10.1016/S0378-1119(98)00309-6. ISSN 0378-1119. PMID 9714768. https://www.sciencedirect.com/science/article/pii/S0378111998003096. 
  4. ↑ "The crystal structure of gankyrin, an oncoprotein found in complexes with cyclin-dependent kinase 4, a 19 S proteasomal ATPase regulator, and the tumor suppressors Rb and p53". The Journal of Biological Chemistry 279 (2): 1541–5. 2004. doi:10.1074/jbc.M310265200. PMID 14573599. 
  5. ↑ "Crystallization of gankyrin, an oncoprotein that interacts with CDK4 and the S6b (rpt3) ATPase of the 19S regulator of the 26S proteasome". Acta Crystallographica Section D 59 (Pt 7): 1294–5. 2003. doi:10.1107/S0907444903009892. PMID 12832791. 
  6. ↑ "The oncoprotein gankyrin negatively regulates both p53 and RB by enhancing proteasomal degradation". Cell Cycle 4 (10): 1335–7. 2005. doi:10.4161/cc.4.10.2107. PMID 16177571. 
  7. ↑ "Entrez Gene: PSMD10 proteasome (prosome, macropain) 26S subunit, non-ATPase, 10". https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=5716. 
  8. ↑ "Perilous journey: a tour of the ubiquitin–proteasome system". Trends in Cell Biology 24 (6): 352–9. Jun 2014. doi:10.1016/j.tcb.2013.12.003. PMID 24457024. 
  9. ↑ "New insights into proteasome function: from archaebacteria to drug development". Chemistry & Biology 2 (8): 503–8. Aug 1995. doi:10.1016/1074-5521(95)90182-5. PMID 9383453. 
  10. ↑ "The Ubiquitin–Proteasome System and Molecular Chaperone Deregulation in Alzheimer's Disease". Molecular Neurobiology 53 (2): 905–31. Jan 2015. doi:10.1007/s12035-014-9063-4. PMID 25561438. 
  11. ↑ "Ubiquitin-proteasome system involvement in Huntington's disease". Frontiers in Molecular Neuroscience 7: 77. 2014. doi:10.3389/fnmol.2014.00077. PMID 25324717. 
  12. ↑ "Proteotoxicity: an underappreciated pathology in cardiac disease". Journal of Molecular and Cellular Cardiology 71: 3–10. Jun 2014. doi:10.1016/j.yjmcc.2013.12.015. PMID 24380730. 
  13. ↑ "Targeting the ubiquitin–proteasome system in heart disease: the basis for new therapeutic strategies". Antioxidants & Redox Signaling 21 (17): 2322–43. Dec 2014. doi:10.1089/ars.2013.5823. PMID 25133688. 
  14. ↑ "Protein quality control and metabolism: bidirectional control in the heart". Cell Metabolism 21 (2): 215–26. Feb 2015. doi:10.1016/j.cmet.2015.01.016. PMID 25651176. 
  15. ↑ 15.0 15.1 "The I kappa B kinase (IKK) and NF-kappa B: key elements of proinflammatory signalling". Seminars in Immunology 12 (1): 85–98. Feb 2000. doi:10.1006/smim.2000.0210. PMID 10723801. 
  16. ↑ "Quality control mechanisms in cellular and systemic DNA damage responses". Ageing Research Reviews 23 (Pt A): 3–11. Sep 2015. doi:10.1016/j.arr.2014.12.009. PMID 25560147. 
  17. ↑ "Role of the proteasome in Alzheimer's disease". Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease 1502 (1): 133–8. Jul 2000. doi:10.1016/s0925-4439(00)00039-9. PMID 10899438. 
  18. ↑ 18.0 18.1 "The role of the ubiquitin-proteasomal pathway in Parkinson's disease and other neurodegenerative disorders". Trends in Neurosciences 24 (11 Suppl): S7–14. Nov 2001. doi:10.1016/s0166-2236(00)01998-6. PMID 11881748. 
  19. ↑ 19.0 19.1 "Morphometrical reappraisal of motor neuron system of Pick's disease and amyotrophic lateral sclerosis with dementia". Acta Neuropathologica 104 (1): 21–8. Jul 2002. doi:10.1007/s00401-001-0513-5. PMID 12070660. 
  20. ↑ "Marked increase in cerebrospinal fluid ubiquitin in Creutzfeldt–Jakob disease". Neuroscience Letters 139 (1): 47–9. May 1992. doi:10.1016/0304-3940(92)90854-z. PMID 1328965. 
  21. ↑ "Limb-girdle muscular dystrophy". Current Neurology and Neuroscience Reports 3 (1): 78–85. Jan 2003. doi:10.1007/s11910-003-0042-9. PMID 12507416. 
  22. ↑ "From neurodegeneration to neurohomeostasis: the role of ubiquitin". Drug News & Perspectives 16 (2): 103–8. Mar 2003. doi:10.1358/dnp.2003.16.2.829327. PMID 12792671. 
  23. ↑ "The ubiquitin proteasome system and myocardial ischemia". American Journal of Physiology. Heart and Circulatory Physiology 304 (3): H337–49. Feb 2013. doi:10.1152/ajpheart.00604.2012. PMID 23220331. 
  24. ↑ "Ubiquitin proteasome dysfunction in human hypertrophic and dilated cardiomyopathies". Circulation 121 (8): 997–1004. Mar 2010. doi:10.1161/CIRCULATIONAHA.109.904557. PMID 20159828. 
  25. ↑ "The ubiquitin–proteasome system in cardiac physiology and pathology". American Journal of Physiology. Heart and Circulatory Physiology 291 (1): H1–H19. Jul 2006. doi:10.1152/ajpheart.00062.2006. PMID 16501026. 
  26. ↑ "Potential for proteasome inhibition in the treatment of cancer". Drug Discovery Today 8 (7): 307–15. Apr 2003. doi:10.1016/s1359-6446(03)02647-3. PMID 12654543. 
  27. ↑ "Regulatory functions of ubiquitination in the immune system". Nature Immunology 3 (1): 20–6. Jan 2002. doi:10.1038/ni0102-20. PMID 11753406. 
  28. ↑ "Circulating proteasomes are markers of cell damage and immunologic activity in autoimmune diseases". The Journal of Rheumatology 29 (10): 2045–52. Oct 2002. PMID 12375310. 
  29. ↑ "Retinoblastoma protein modulates gankyrin-MDM2 in regulation of p53 stability and chemosensitivity in cancer cells". Oncogene 27 (29): 4034–43. Jul 2008. doi:10.1038/onc.2008.43. PMID 18332869. 
  30. ↑ 30.0 30.1 "Large-scale mapping of human protein-protein interactions by mass spectrometry". Mol. Syst. Biol. 3: 89. 2007. doi:10.1038/msb4100134. PMID 17353931. 
  31. ↑ "Towards a proteome-scale map of the human protein-protein interaction network". Nature 437 (7062): 1173–8. Oct 2005. doi:10.1038/nature04209. PMID 16189514. Bibcode: 2005Natur.437.1173R. 
  32. ↑ "Gankyrin is an ankyrin-repeat oncoprotein that interacts with CDK4 kinase and the S6 ATPase of the 26 S proteasome". J. Biol. Chem. 277 (13): 10893–902. Mar 2002. doi:10.1074/jbc.M107313200. PMID 11779854. 

Further reading

External links



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