PSMD7 explained

26S proteasome non-ATPase regulatory subunit 7, also known as 26S proteasome non-ATPase subunit Rpn8, is an enzyme that in humans is encoded by the PSMD7 gene.[1]

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.

Gene

The gene PSMD7 encodes a non-ATPase subunit of the 19S regulator. A pseudogene has been identified on chromosome 17.[2] The human gene PSMD7 has 7 Exons and locates at chromosome band 16q22.3.

Protein

The human protein 26S proteasome non-ATPase regulatory subunit 14 is 37 kDa in size and composed of 324 amino acids. The calculated theoretical pI of this protein is 6.11.[3]

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).s The lid sub complex of 19S regulatory particle consisted of 9 subunits. The assembly of 19S lid is independent to the assembly process of 19S base. Two assembly modules, Rpn5-Rpn6-Rpn8-Rpn9-Rpn11 modules and Rpn3-Rpn7-SEM1 modules were identified during 19S lid assembly using yeast proteasome as a model complex.[4] [5] [6] [7] The subunit Rpn12 incorporated into 19S regulatory particle when 19S lid and base bind together.[8] Recent evidence of crystal structures of proteasomes isolated from Saccharomyces cerevisiae suggests that the catalytically active subunit Rpn8 and subunit Rpn11 form heterodimer. The data also reveals the details of the Rpn11 active site and the mode of interaction with other subunits.[9]

Function

As the degradation machinery that is responsible for ~70% of intracellular proteolysis,[10] 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.

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) [11] 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.[12] 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,[13] [14] cardiovascular diseases,[15] [16] [17] inflammatory responses and autoimmune diseases,[18] and systemic DNA damage responses leading to malignancies.[19]

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,[20] Parkinson's disease[21] and Pick's disease,[22] Amyotrophic lateral sclerosis (ALS),[22] Huntington's disease,[21] Creutzfeldt–Jakob disease,[23] and motor neuron diseases, polyglutamine (PolyQ) diseases, Muscular dystrophies[24] and several rare forms of neurodegenerative diseases associated with dementia.[25] As part of the ubiquitin–proteasome system (UPS), the proteasome maintains cardiac protein homeostasis and thus plays a significant role in cardiac ischemic injury,[26] ventricular hypertrophy[27] and heart failure.[28] 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.[29] 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).[30] 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.[31] Lastly, autoimmune disease patients with SLE, Sjögren syndrome and rheumatoid arthritis (RA) predominantly exhibit circulating proteasomes which can be applied as clinical biomarkers.[32]

Further reading

Notes and References

  1. Tsurumi C, DeMartino GN, Slaughter CA, Shimbara N, Tanaka K . cDNA cloning of p40, a regulatory subunit of the human 26S proteasome, and a homolog of the Mov-34 gene product . Biochemical and Biophysical Research Communications . 210 . 2 . 600–8 . May 1995 . 7755639 . 10.1006/bbrc.1995.1701 .
  2. Web site: Entrez Gene: PSMD7 proteasome (prosome, macropain) 26S subunit, non-ATPase, 7 (Mov34 homolog).
  3. Web site: Uniprot: P51665 - PSMD7_HUMAN.
  4. Le Tallec B, Barrault MB, Guérois R, Carré T, Peyroche A . Hsm3/S5b participates in the assembly pathway of the 19S regulatory particle of the proteasome . Molecular Cell . 33 . 3 . 389–99 . Feb 2009 . 19217412 . 10.1016/j.molcel.2009.01.010 . free .
  5. Gödderz D, Dohmen RJ . Hsm3/S5b joins the ranks of 26S proteasome assembly chaperones . Molecular Cell . 33 . 4 . 415–6 . Feb 2009 . 19250902 . 10.1016/j.molcel.2009.02.007 . free .
  6. Isono E, Nishihara K, Saeki Y, Yashiroda H, Kamata N, Ge L, Ueda T, Kikuchi Y, Tanaka K, Nakano A, Toh-e A . The assembly pathway of the 19S regulatory particle of the yeast 26S proteasome . Molecular Biology of the Cell . 18 . 2 . 569–80 . Feb 2007 . 17135287 . 1783769 . 10.1091/mbc.E06-07-0635 .
  7. Fukunaga K, Kudo T, Toh-e A, Tanaka K, Saeki Y . Dissection of the assembly pathway of the proteasome lid in Saccharomyces cerevisiae . Biochemical and Biophysical Research Communications . 396 . 4 . 1048–53 . Jun 2010 . 20471955 . 10.1016/j.bbrc.2010.05.061 .
  8. Tomko RJ, Hochstrasser M . Incorporation of the Rpn12 subunit couples completion of proteasome regulatory particle lid assembly to lid-base joining . Molecular Cell . 44 . 6 . 907–17 . Dec 2011 . 22195964 . 3251515 . 10.1016/j.molcel.2011.11.020 .
  9. Pathare GR, Nagy I, Śledź P, Anderson DJ, Zhou HJ, Pardon E, Steyaert J, Förster F, Bracher A, Baumeister W . Crystal structure of the proteasomal deubiquitylation module Rpn8-Rpn11 . Proceedings of the National Academy of Sciences of the United States of America . 111 . 8 . 2984–9 . Feb 2014 . 24516147 . 3939901 . 10.1073/pnas.1400546111 . 2014PNAS..111.2984P . free .
  10. Rock KL, Gramm C, Rothstein L, Clark K, Stein R, Dick L, Hwang D, Goldberg AL . 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 . Sep 1994 . 8087844 . 10.1016/s0092-8674(94)90462-6. 22262916 .
  11. Kleiger G, Mayor T . Perilous journey: a tour of the ubiquitin–proteasome system . Trends in Cell Biology . 24 . 6 . 352–9 . Jun 2014 . 24457024 . 4037451 . 10.1016/j.tcb.2013.12.003 .
  12. Goldberg. AL. Stein. R. Adams. J. New insights into proteasome function: from archaebacteria to drug development.. Chemistry & Biology. August 1995. 2. 8. 503–8. 9383453. 10.1016/1074-5521(95)90182-5. free.
  13. Sulistio YA, Heese K . The Ubiquitin–Proteasome System and Molecular Chaperone Deregulation in Alzheimer's Disease . Molecular Neurobiology . Jan 2015 . 25561438 . 10.1007/s12035-014-9063-4 . 53 . 2 . 905–31. 14103185 .
  14. Ortega Z, Lucas JJ . Ubiquitin–proteasome system involvement in Huntington's disease . Frontiers in Molecular Neuroscience . 7 . 77 . 2014 . 25324717 . 4179678 . 10.3389/fnmol.2014.00077 . free .
  15. Sandri M, Robbins J . Proteotoxicity: an underappreciated pathology in cardiac disease . Journal of Molecular and Cellular Cardiology . 71 . 3–10 . Jun 2014 . 24380730 . 4011959 . 10.1016/j.yjmcc.2013.12.015 .
  16. Drews O, Taegtmeyer H . Targeting the ubiquitin-proteasome system in heart disease: the basis for new therapeutic strategies . Antioxidants & Redox Signaling . 21 . 17 . 2322–43 . Dec 2014 . 25133688 . 4241867 . 10.1089/ars.2013.5823 .
  17. Wang ZV, Hill JA . Protein quality control and metabolism: bidirectional control in the heart . Cell Metabolism . 21 . 2 . 215–26 . Feb 2015 . 25651176 . 4317573 . 10.1016/j.cmet.2015.01.016 .
  18. 10723801. 2000. Karin. M. The I kappa B kinase (IKK) and NF-kappa B: Key elements of proinflammatory signalling. Seminars in Immunology. 12. 1. 85–98. Delhase. M. 10.1006/smim.2000.0210.
  19. Ermolaeva MA, Dakhovnik A, Schumacher B . Quality control mechanisms in cellular and systemic DNA damage responses . Ageing Research Reviews . 23 . Pt A . 3–11 . Jan 2015 . 25560147 . 10.1016/j.arr.2014.12.009 . 4886828.
  20. Checler. F. da Costa. CA. Ancolio. K. Chevallier. N. Lopez-Perez. E. Marambaud. P. Role of the proteasome in Alzheimer's disease.. Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease. 26 July 2000. 1502. 1. 133–8. 10899438. 10.1016/s0925-4439(00)00039-9. free.
  21. Chung. KK. Dawson. VL. Dawson. TM. The role of the ubiquitin-proteasomal pathway in Parkinson's disease and other neurodegenerative disorders.. Trends in Neurosciences. November 2001. 24. 11 Suppl. S7–14. 11881748. 10.1016/s0166-2236(00)01998-6. 2211658.
  22. Ikeda. K. Akiyama. H. Arai. T. Ueno. H. Tsuchiya. K. Kosaka. K. Morphometrical reappraisal of motor neuron system of Pick's disease and amyotrophic lateral sclerosis with dementia.. Acta Neuropathologica. July 2002. 104. 1. 21–8. 12070660. 10.1007/s00401-001-0513-5. 22396490.
  23. Manaka. H. Kato. T. Kurita. K. Katagiri. T. Shikama. Y. Kujirai. K. Kawanami. T. Suzuki. Y. Nihei. K. Sasaki. H. Marked increase in cerebrospinal fluid ubiquitin in Creutzfeldt–Jakob disease.. Neuroscience Letters. 11 May 1992. 139. 1. 47–9. 1328965. 10.1016/0304-3940(92)90854-z. 28190967.
  24. Mathews. KD. Moore. SA. Limb-girdle muscular dystrophy.. Current Neurology and Neuroscience Reports. January 2003. 3. 1. 78–85. 12507416. 10.1007/s11910-003-0042-9. 5780576.
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  26. 23220331. 3774499. 2013. Calise. J. The ubiquitin proteasome system and myocardial ischemia. AJP: Heart and Circulatory Physiology. 304. 3. H337–49. Powell. S. R.. 10.1152/ajpheart.00604.2012.
  27. Predmore. JM. Wang. P. Davis. F. Bartolone. S. Westfall. MV. Dyke. DB. Pagani. F. Powell. SR. Day. SM. Ubiquitin proteasome dysfunction in human hypertrophic and dilated cardiomyopathies.. Circulation. 2 March 2010. 121. 8. 997–1004. 20159828. 10.1161/circulationaha.109.904557. 2857348.
  28. Powell. SR. The ubiquitin-proteasome system in cardiac physiology and pathology. American Journal of Physiology. Heart and Circulatory Physiology. July 2006. 291. 1. H1–H19. 16501026. 10.1152/ajpheart.00062.2006. 7073263 .
  29. Adams. J. Potential for proteasome inhibition in the treatment of cancer.. Drug Discovery Today. 1 April 2003. 8. 7. 307–15. 12654543. 10.1016/s1359-6446(03)02647-3.
  30. Karin. M. Delhase. M. The I kappa B kinase (IKK) and NF-kappa B: key elements of proinflammatory signalling.. Seminars in Immunology. February 2000. 12. 1. 85–98. 10723801. 10.1006/smim.2000.0210.
  31. Ben-Neriah. Y. Regulatory functions of ubiquitination in the immune system. Nature Immunology. January 2002. 3. 1. 20–6. 11753406. 10.1038/ni0102-20. 26973319.
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