PSMD1: Difference between revisions

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{{Infobox_gene}}
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'''26S proteasome non-ATPase regulatory subunit 1''', also as known as '''26S Proteasome Regulatory Subunit Rpn2''' (systematic nomenclature),  is a [[protein]] that in humans is encoded by the ''PSMD1'' [[gene]].<ref name="pmid8816993">{{cite journal | vauthors = Yokota K, Kagawa S, Shimizu Y, Akioka H, Tsurumi C, Noda C, Fujimuro M, Yokosawa H, Fujiwara T, Takahashi E, Ohba M, Yamasaki M, DeMartino GN, Slaughter CA, Toh-e A, Tanaka K | title = CDNA cloning of p112, the largest regulatory subunit of the human 26s proteasome, and functional analysis of its yeast homologue, sen3p | journal = Molecular Biology of the Cell | volume = 7 | issue = 6 | pages = 853–70 | date = Jun 1996 | pmid = 8816993 | pmc = 275938 | doi = 10.1091/mbc.7.6.853 }}</ref><ref name="entrez">{{cite web | title = Entrez Gene: PSMD1 proteasome (prosome, macropain) 26S subunit, non-ATPase, 1| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=5707| accessdate = }}</ref> This protein is one of the 19 essential subunits that contributes to the complete assembly of 19S proteasome complex.<ref>{{cite journal | vauthors = Gu ZC, Enenkel C | title = Proteasome assembly | journal = Cellular and Molecular Life Sciences | volume = 71 | issue = 24 | pages = 4729–45 | date = Dec 2014 | pmid = 25107634 | doi = 10.1007/s00018-014-1699-8 }}</ref>
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<!-- The GNF_Protein_box is automatically maintained by Protein Box Bot.  See Template:PBB_Controls to Stop updates. -->
==Structure==
{{GNF_Protein_box
| image =
| image_source =
| PDB =  
| Name = Proteasome (prosome, macropain) 26S subunit, non-ATPase, 1
| HGNCid = 9554
| Symbol = PSMD1
| AltSymbols =; MGC133040; MGC133041; P112; S1
| OMIM = 
| ECnumber = 
| Homologene = 2100
| MGIid = 1917497
| GeneAtlas_image1 = PBB_GE_PSMD1_201198_s_at_tn.png
| GeneAtlas_image2 = PBB_GE_PSMD1_201199_s_at_tn.png
| Function = {{GNF_GO|id=GO:0005488 |text = binding}}
| Component = {{GNF_GO|id=GO:0005829 |text = cytosol}} {{GNF_GO|id=GO:0005838 |text = proteasome regulatory particle (sensu Eukaryota)}}
| Process = {{GNF_GO|id=GO:0000074 |text = regulation of progression through cell cycle}}
| Orthologs = {{GNF_Ortholog_box
    | Hs_EntrezGene = 5707
    | Hs_Ensembl = ENSG00000173692
    | Hs_RefseqProtein = NP_002798
    | Hs_RefseqmRNA = NM_002807
    | Hs_GenLoc_db = 
    | Hs_GenLoc_chr = 2
    | Hs_GenLoc_start = 231629836
    | Hs_GenLoc_end = 231745712
    | Hs_Uniprot = Q99460
    | Mm_EntrezGene = 70247
    | Mm_Ensembl = ENSMUSG00000026229
    | Mm_RefseqmRNA = NM_027357
    | Mm_RefseqProtein = NP_081633
    | Mm_GenLoc_db = 
    | Mm_GenLoc_chr = 1
    | Mm_GenLoc_start = 87895790
    | Mm_GenLoc_end = 87970466
    | Mm_Uniprot = A0JLU3
  }}
}}
'''Proteasome (prosome, macropain) 26S subunit, non-ATPase, 1''', also known as '''PSMD1''', is a human [[gene]].<ref name="entrez">{{cite web | title = Entrez Gene: PSMD1 proteasome (prosome, macropain) 26S subunit, non-ATPase, 1| url = http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=5707| accessdate = }}</ref>


<!-- The PBB_Summary template is automatically maintained by Protein Box Bot.  See Template:PBB_Controls to Stop updates. -->
=== Gene expression===
{{PBB_Summary
The gene ''PSMD1'' encodes the largest non-ATPase subunit of the 19S regulator base, which is responsible for substrate recognition and binding.<ref name="entrez"/> The human PSMD1 gene has 25 exons and locates at chromosome band 2q37.1. The human protein '''26S proteasome non-ATPase regulatory subunit 1''' is 106 kDa in size and composed of 953 amino acids. The calculated theoretical pI of this protein is 5.25. An alternative splicing during gene expression generates an isoform of the protein in which the amino acid sequence from 797-827 is missing.
| section_title =  
| summary_text = 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 the largest non-ATPase subunit of the 19S regulator lid, which is responsible for substrate recognition and binding.<ref name="entrez">{{cite web | title = Entrez Gene: PSMD1 proteasome (prosome, macropain) 26S subunit, non-ATPase, 1| url = http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=5707| accessdate = }}</ref>
}}


==References==
=== Complex assembly ===
{{reflist|2}}
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).  '''Protein 26S proteasome non-ATPase regulatory subunit 1''' (Rpn2) is an essential component of forming the base sub complex of 19S regulatory particle. Traditionally, Rpn1 and Rpn2 were considered residing at the center of base sub complex and surrounded by six AAA ATPases (Rpt 1-6). However, recent investigation provides an alternative structure of 19S base via an integrative approach combining data from cryoelectron microscopy, X-ray crystallography, residue-specific chemical cross-linking, and several proteomics techniques. Rpn2 is rigid protein located on the side of ATPase ring, supporting as the connection between the lid and base. Rpn1 is conformationally variable, positioned at the periphery of the ATPase ring. The ubiquitin receptors Rpn10 and Rpn13 are located further in the distal part of the 19S complex, indicating that they were recruited to the complex late during the assembly process.<ref>{{cite journal | vauthors = Lasker K, Förster F, Bohn S, Walzthoeni T, Villa E, Unverdorben P, Beck F, Aebersold R, Sali A, Baumeister W | title = Molecular architecture of the 26S proteasome holocomplex determined by an integrative approach | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 109 | issue = 5 | pages = 1380–7 | date = Jan 2012 | pmid = 22307589 | pmc = 3277140 | doi = 10.1073/pnas.1120559109 | bibcode = 2012PNAS..109.1380L }}</ref>
==Further reading==
 
{{refbegin | 2}}
== Function ==
{{PBB_Further_reading
As the degradation machinery that is responsible for ~70% of intracellular proteolysis,<ref>{{cite journal | vauthors = Rock KL, Gramm C, Rothstein L, Clark K, Stein R, Dick L, Hwang D, Goldberg AL | title = Inhibitors of the proteasome block the degradation of most cell proteins and the generation of peptides presented on MHC class I molecules | journal = Cell | volume = 78 | issue = 5 | pages = 761–71 | date = Sep 1994 | pmid = 8087844 | doi=10.1016/s0092-8674(94)90462-6}}</ref> 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. Rpn2 is the largest subunit of 19S regulatory particle and stays at the center of the "base" subcomplex of 19S particle.
| citations =
 
*{{cite journal  | author=Coux O, Tanaka K, Goldberg AL |title=Structure and functions of the 20S and 26S proteasomes. |journal=Annu. Rev. Biochem. |volume=65 |issue=  |pages= 801-47 |year= 1996 |pmid= 8811196 |doi= 10.1146/annurev.bi.65.070196.004101 }}
== Clinical significance ==
*{{cite journal | author=Goff SP |title=Death by deamination: a novel host restriction system for HIV-1. |journal=Cell |volume=114 |issue= 3 |pages= 281-3 |year= 2003 |pmid= 12914693 |doi=  }}
 
*{{cite journal  | author=Yokota K, Kagawa S, Shimizu Y, ''et al.'' |title=CDNA cloning of p112, the largest regulatory subunit of the human 26s proteasome, and functional analysis of its yeast homologue, sen3p. |journal=Mol. Biol. Cell |volume=7 |issue= 6 |pages= 853-70 |year= 1997 |pmid= 8816993 |doi= }}
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.
*{{cite journal  | author=Seeger M, Ferrell K, Frank R, Dubiel W |title=HIV-1 tat inhibits the 20 S proteasome and its 11 S regulator-mediated activation. |journal=J. Biol. Chem. |volume=272 |issue= 13 |pages= 8145-8 |year= 1997 |pmid= 9079628 |doi= }}
 
*{{cite journal | author=Madani N, Kabat D |title=An endogenous inhibitor of human immunodeficiency virus in human lymphocytes is overcome by the viral Vif protein. |journal=J. Virol. |volume=72 |issue= 12 |pages= 10251-5 |year= 1998 |pmid= 9811770 |doi= }}
The proteasomes form a pivotal component for the [[proteasome|Ubiquitin-Proteasome System (UPS)]] <ref>{{cite journal | vauthors = Kleiger G, Mayor T | title = Perilous journey: a tour of the ubiquitin-proteasome system | journal = Trends in Cell Biology | volume = 24 | issue = 6 | pages = 352–9 | date = Jun 2014 | pmid = 24457024 | pmc = 4037451 | doi = 10.1016/j.tcb.2013.12.003 }}</ref> 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]].<ref>{{cite journal | vauthors = Goldberg AL, Stein R, Adams J | title = New insights into proteasome function: from archaebacteria to drug development | journal = Chemistry & Biology | volume = 2 | issue = 8 | pages = 503–8 | date = Aug 1995 | pmid = 9383453 | doi=10.1016/1074-5521(95)90182-5}}</ref> 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,<ref>{{cite journal | vauthors = Sulistio YA, Heese K | title = The Ubiquitin-Proteasome System and Molecular Chaperone Deregulation in Alzheimer's Disease | journal = Molecular Neurobiology | date = Jan 2015 | pmid = 25561438 | doi = 10.1007/s12035-014-9063-4 | volume=53 | pages=905–31}}</ref><ref>{{cite journal | vauthors = Ortega Z, Lucas JJ | title = Ubiquitin-proteasome system involvement in Huntington's disease | journal = Frontiers in Molecular Neuroscience | volume = 7 | pages = 77 | date = 2014 | pmid = 25324717 | pmc = 4179678 | doi = 10.3389/fnmol.2014.00077 }}</ref> cardiovascular diseases,<ref>{{cite journal | vauthors = Sandri M, Robbins J | title = Proteotoxicity: an underappreciated pathology in cardiac disease | journal = Journal of Molecular and Cellular Cardiology | volume = 71 | pages = 3–10 | date = Jun 2014 | pmid = 24380730 | pmc = 4011959 | doi = 10.1016/j.yjmcc.2013.12.015 }}</ref><ref>{{cite journal | vauthors = Drews O, Taegtmeyer H | title = Targeting the ubiquitin-proteasome system in heart disease: the basis for new therapeutic strategies | journal = Antioxidants & Redox Signaling | volume = 21 | issue = 17 | pages = 2322–43 | date = Dec 2014 | pmid = 25133688 | pmc = 4241867 | doi = 10.1089/ars.2013.5823 }}</ref><ref>{{cite journal | vauthors = Wang ZV, Hill JA | title = Protein quality control and metabolism: bidirectional control in the heart | journal = Cell Metabolism | volume = 21 | issue = 2 | pages = 215–26 | date = Feb 2015 | pmid = 25651176 | pmc = 4317573 | doi = 10.1016/j.cmet.2015.01.016 }}</ref> inflammatory responses and autoimmune diseases,<ref name = "Karin_2000">{{cite journal | vauthors = Karin M, Delhase M | title = The I kappa B kinase (IKK) and NF-kappa B: key elements of proinflammatory signalling | journal = Seminars in Immunology | volume = 12 | issue = 1 | pages = 85–98 | date = Feb 2000 | pmid = 10723801 | doi = 10.1006/smim.2000.0210 }}</ref> and systemic DNA damage responses leading to [[malignancies]].<ref>{{cite journal | vauthors = Ermolaeva MA, Dakhovnik A, Schumacher B | title = Quality control mechanisms in cellular and systemic DNA damage responses | journal = Ageing Research Reviews | volume = 23 | issue = Pt A | pages = 3–11 | date = Sep 2015 | pmid = 25560147 | doi = 10.1016/j.arr.2014.12.009 | pmc=4886828}}</ref>
*{{cite journal  | author=Simon JH, Gaddis NC, Fouchier RA, Malim MH |title=Evidence for a newly discovered cellular anti-HIV-1 phenotype. |journal=Nat. Med. |volume=4 |issue= 12 |pages= 1397-400 |year= 1998 |pmid= 9846577 |doi= 10.1038/3987 }}
 
*{{cite journal | author=Lüders J, Demand J, Höhfeld J |title=The ubiquitin-related BAG-1 provides a link between the molecular chaperones Hsc70/Hsp70 and the proteasome. |journal=J. Biol. Chem. |volume=275 |issue= 7 |pages= 4613-7 |year= 2000 |pmid= 10671488 |doi=  }}
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]],<ref>{{cite journal | vauthors = Checler F, da Costa CA, Ancolio K, Chevallier N, Lopez-Perez E, Marambaud P | title = Role of the proteasome in Alzheimer's disease | journal = Biochimica et Biophysica Acta | volume = 1502 | issue = 1 | pages = 133–8 | date = Jul 2000 | pmid = 10899438 | doi=10.1016/s0925-4439(00)00039-9}}</ref> [[Parkinson's disease]]<ref name="ReferenceA">{{cite journal | vauthors = Chung KK, Dawson VL, Dawson TM | title = The role of the ubiquitin-proteasomal pathway in Parkinson's disease and other neurodegenerative disorders | journal = Trends in Neurosciences | volume = 24 | issue = 11 Suppl | pages = S7–14 | date = Nov 2001 | pmid = 11881748 | doi=10.1016/s0166-2236(00)01998-6}}</ref> and [[Pick's disease]],<ref name="ReferenceB">{{cite journal | vauthors = Ikeda K, Akiyama H, Arai T, Ueno H, Tsuchiya K, Kosaka K | title = Morphometrical reappraisal of motor neuron system of Pick's disease and amyotrophic lateral sclerosis with dementia | journal = Acta Neuropathologica | volume = 104 | issue = 1 | pages = 21–8 | date = Jul 2002 | pmid = 12070660 | doi = 10.1007/s00401-001-0513-5 }}</ref> [[Amyotrophic lateral sclerosis]] ([[ALS]]),<ref name="ReferenceB"/> [[Huntington's disease]],<ref name="ReferenceA"/> [[Creutzfeldt–Jakob disease]],<ref>{{cite journal | vauthors = Manaka H, Kato T, Kurita K, Katagiri T, Shikama Y, Kujirai K, Kawanami T, Suzuki Y, Nihei K, Sasaki H | title = Marked increase in cerebrospinal fluid ubiquitin in Creutzfeldt–Jakob disease | journal = Neuroscience Letters | volume = 139 | issue = 1 | pages = 47–9 | date = May 1992 | pmid = 1328965 | doi=10.1016/0304-3940(92)90854-z}}</ref> and motor neuron diseases, polyglutamine (PolyQ) diseases, [[Muscular dystrophies]]<ref>{{cite journal | vauthors = Mathews KD, Moore SA | title = Limb-girdle muscular dystrophy | journal = Current Neurology and Neuroscience Reports | volume = 3 | issue = 1 | pages = 78–85 | date = Jan 2003 | pmid = 12507416 | doi=10.1007/s11910-003-0042-9}}</ref> and several rare forms of neurodegenerative diseases associated with [[dementia]].<ref>{{cite journal | vauthors = Mayer RJ | title = From neurodegeneration to neurohomeostasis: the role of ubiquitin | journal = Drug News & Perspectives | volume = 16 | issue = 2 | pages = 103–8 | date = Mar 2003 | pmid = 12792671 | doi=10.1358/dnp.2003.16.2.829327}}</ref> As part of the [[proteasome|Ubiquitin-Proteasome System (UPS)]], the proteasome maintains cardiac protein homeostasis and thus plays a significant role in cardiac [[Ischemic]] injury,<ref>{{cite journal | vauthors = Calise J, Powell SR | title = The ubiquitin proteasome system and myocardial ischemia | journal = American Journal of Physiology. Heart and Circulatory Physiology | volume = 304 | issue = 3 | pages = H337–49 | date = Feb 2013 | pmid = 23220331 | pmc = 3774499 | doi = 10.1152/ajpheart.00604.2012 }}</ref> [[ventricular hypertrophy]]<ref>{{cite journal | vauthors = Predmore JM, Wang P, Davis F, Bartolone S, Westfall MV, Dyke DB, Pagani F, Powell SR, Day SM | title = Ubiquitin proteasome dysfunction in human hypertrophic and dilated cardiomyopathies | journal = Circulation | volume = 121 | issue = 8 | pages = 997–1004 | date = Mar 2010 | pmid = 20159828 | pmc = 2857348 | doi = 10.1161/CIRCULATIONAHA.109.904557 }}</ref> and [[Heart failure]].<ref>{{cite journal | vauthors = Powell SR | title = The ubiquitin-proteasome system in cardiac physiology and pathology | journal = American Journal of Physiology. Heart and Circulatory Physiology | volume = 291 | issue = 1 | pages = H1–H19 | date = Jul 2006 | pmid = 16501026 | doi = 10.1152/ajpheart.00062.2006 }}</ref> 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.<ref>{{cite journal | vauthors = Adams J | title = Potential for proteasome inhibition in the treatment of cancer | journal = Drug Discovery Today | volume = 8 | issue = 7 | pages = 307–15 | date = Apr 2003 | pmid = 12654543 | doi=10.1016/s1359-6446(03)02647-3}}</ref> Moreover, the UPS regulates the degradation of tumor suppressor gene products such as [[adenomatous polyposis coli]] ([[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 kinase|Raf]], [[Myc]], [[MYB (gene)|Myb]], [[NF-κB|Rel]], [[Src (gene)|Src]], [[MOS (gene)|Mos]], [[Abl (gene)|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, [[Interleukin 8|IL-8]], [[adhesion molecules]] ([[ICAM-1]], [[VCAM-1]], P selectine) and [[prostaglandins]] and [[nitric oxide]] (NO)<ref name = "Karin_2000"/> Additionally, the UPS also plays a role in inflammatory responses as regulators of leukocyte proliferation, mainly through proteolysis of cyclines and the degradation of [[Cyclin-dependent kinase|CDK]] inhibitors.<ref>{{cite journal | vauthors = Ben-Neriah Y | title = Regulatory functions of ubiquitination in the immune system | journal = Nature Immunology | volume = 3 | issue = 1 | pages = 20–6 | date = Jan 2002 | pmid = 11753406 | doi = 10.1038/ni0102-20 }}</ref> Lastly, [[autoimmune disease]] patients with [[Systemic lupus erythematosus|SLE]], [[Sjogren's syndrome]] and [[rheumatoid arthritis]] (RA) predominantly exhibit circulating proteasomes which can be applied as clinical biomarkers.<ref>{{cite journal | vauthors = Egerer K, Kuckelkorn U, Rudolph PE, Rückert JC, Dörner T, Burmester GR, Kloetzel PM, Feist E | title = Circulating proteasomes are markers of cell damage and immunologic activity in autoimmune diseases | journal = The Journal of Rheumatology | volume = 29 | issue = 10 | pages = 2045–52 | date = Oct 2002 | pmid = 12375310 }}</ref>
*{{cite journal  | author=Mulder LC, Muesing MA |title=Degradation of HIV-1 integrase by the N-end rule pathway. |journal=J. Biol. Chem. |volume=275 |issue= 38 |pages= 29749-53 |year= 2000 |pmid= 10893419 |doi= 10.1074/jbc.M004670200 }}
 
*{{cite journal | author=Sheehy AM, Gaddis NC, Choi JD, Malim MH |title=Isolation of a human gene that inhibits HIV-1 infection and is suppressed by the viral Vif protein. |journal=Nature |volume=418 |issue= 6898 |pages= 646-50 |year= 2002 |pmid= 12167863 |doi= 10.1038/nature00939 }}
A clinical study on patients with age related [[macula degeneration]] identified four significant proteins, including 26S proteasome non-ATPase regulatory subunit 1 ([[Rpn2]]), that were increased, according to semi-quantitative proteomic profiling. The study reported that an LC-MRM assay revealed a significant increase of Rpn2 in 15 macula degeneration patients compared to the control subjects, suggesting that this protein could be a biomarker for this condition.<ref name="Lee_2014">{{cite journal | vauthors = Lee H, Choi AJ, Kang GY, Park HS, Kim HC, Lim HJ, Chung H | title = Increased 26S proteasome non-ATPase regulatory subunit 1 in the aqueous humor of patients with age-related macular degeneration | journal = BMB Reports | volume = 47 | issue = 5 | pages = 292–7 | date = May 2014 | pmid = 24286321 | pmc = 4163863 | doi=10.5483/bmbrep.2014.47.5.193}}</ref> Age-related macular degeneration is the leading cause of blindness in the world. Evidence is accumulating that the suppression of the UPS contributes to the increase of toxic proteins and inflammation in [[retina]] pigment epithelium, the functional abnormalities and/or the degeneration of which are believed to be the initiators and major pathologies of macula degeneration.<ref name = "Pickart_2001">{{cite journal | vauthors = Pickart CM | title = Mechanisms underlying ubiquitination | journal = Annual Review of Biochemistry | volume = 70 | pages = 503–33 | date = 2001 | pmid = 11395416 | doi = 10.1146/annurev.biochem.70.1.503 }}</ref> There are only limited options for the treatment of macular degeneration, thus early identification of susceptibility and preventive measures are important therapeutic strategies. New potential biomarkers for neovascular macular degeneratuon and UPS-related proteins that are altered in patients such as Rpn2 may serve as the basis for future clinical studies to determine target proteins involved in the protection of the eye against macula degeneration.<ref name="Lee_2014"/><ref name = "Pickart_2001"/>
*{{cite journal  | author=Huang X, Seifert U, Salzmann U, ''et al.'' |title=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=J. Mol. Biol. |volume=323 |issue= 4 |pages= 771-82 |year= 2002 |pmid= 12419264 |doi= }}
 
*{{cite journal | author=Strausberg RL, Feingold EA, Grouse LH, ''et al.'' |title=Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=99 |issue= 26 |pages= 16899-903 |year= 2003 |pmid= 12477932 |doi= 10.1073/pnas.242603899 }}
== References ==
*{{cite journal | author=Gaddis NC, Chertova E, Sheehy AM, ''et al.'' |title=Comprehensive investigation of the molecular defect in vif-deficient human immunodeficiency virus type 1 virions. |journal=J. Virol. |volume=77 |issue= 10 |pages= 5810-20 |year= 2003 |pmid= 12719574 |doi= }}
{{reflist|33em}}
*{{cite journal | author=Lecossier D, Bouchonnet F, Clavel F, Hance AJ |title=Hypermutation of HIV-1 DNA in the absence of the Vif protein. |journal=Science |volume=300 |issue= 5622 |pages= 1112 |year= 2003 |pmid= 12750511 |doi= 10.1126/science.1083338 }}
 
*{{cite journal | author=Zhang H, Yang B, Pomerantz RJ, ''et al.'' |title=The cytidine deaminase CEM15 induces hypermutation in newly synthesized HIV-1 DNA. |journal=Nature |volume=424 |issue= 6944 |pages= 94-8 |year= 2003 |pmid= 12808465 |doi= 10.1038/nature01707 }}
== Further reading ==
*{{cite journal | author=Mangeat B, Turelli P, Caron G, ''et al.'' |title=Broad antiretroviral defence by human APOBEC3G through lethal editing of nascent reverse transcripts. |journal=Nature |volume=424 |issue= 6944 |pages= 99-103 |year= 2003 |pmid= 12808466 |doi= 10.1038/nature01709 }}
{{refbegin|33em}}
*{{cite journal | author=Harris RS, Bishop KN, Sheehy AM, ''et al.'' |title=DNA deamination mediates innate immunity to retroviral infection. |journal=Cell |volume=113 |issue= 6 |pages= 803-9 |year= 2003 |pmid= 12809610 |doi= }}
* {{cite journal | vauthors = Coux O, Tanaka K, Goldberg AL | title = Structure and functions of the 20S and 26S proteasomes | journal = Annual Review of Biochemistry | volume = 65 | issue =  | pages = 801–47 | year = 1996 | pmid = 8811196 | doi = 10.1146/annurev.bi.65.070196.004101 }}
*{{cite journal | author=Harris RS, Sheehy AM, Craig HM, ''et al.'' |title=DNA deamination: not just a trigger for antibody diversification but also a mechanism for defense against retroviruses. |journal=Nat. Immunol. |volume=4 |issue= 7 |pages= 641-3 |year= 2003 |pmid= 12830140 |doi= 10.1038/ni0703-641 }}
* {{cite journal | vauthors = Goff SP | title = Death by deamination: a novel host restriction system for HIV-1 | journal = Cell | volume = 114 | issue = 3 | pages = 281–3 | date = Aug 2003 | pmid = 12914693 | doi = 10.1016/S0092-8674(03)00602-0 }}
*{{cite journal | author=Gu Y, Sundquist WI |title=Good to CU. |journal=Nature |volume=424 |issue= 6944 |pages= 21-2 |year= 2003 |pmid= 12840737 |doi= 10.1038/424021a }}
* {{cite journal | vauthors = Seeger M, Ferrell K, Frank R, Dubiel W | title = HIV-1 tat inhibits the 20 S proteasome and its 11 S regulator-mediated activation | journal = The Journal of Biological Chemistry | volume = 272 | issue = 13 | pages = 8145–8 | date = Mar 1997 | pmid = 9079628 | doi = 10.1074/jbc.272.13.8145 }}
*{{cite journal | author=Mariani R, Chen D, Schröfelbauer B, ''et al.'' |title=Species-specific exclusion of APOBEC3G from HIV-1 virions by Vif. |journal=Cell |volume=114 |issue= 1 |pages= 21-31 |year= 2003 |pmid= 12859895 |doi= }}
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* {{cite journal | vauthors = Simon JH, Gaddis NC, Fouchier RA, Malim MH | title = Evidence for a newly discovered cellular anti-HIV-1 phenotype | journal = Nature Medicine | volume = 4 | issue = 12 | pages = 1397–400 | date = Dec 1998 | pmid = 9846577 | doi = 10.1038/3987 }}
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* {{cite journal | vauthors = Mulder LC, Muesing MA | title = Degradation of HIV-1 integrase by the N-end rule pathway | journal = The Journal of Biological Chemistry | volume = 275 | issue = 38 | pages = 29749–53 | date = Sep 2000 | pmid = 10893419 | doi = 10.1074/jbc.M004670200 }}
* {{cite journal | vauthors = Sheehy AM, Gaddis NC, Choi JD, Malim MH | title = Isolation of a human gene that inhibits HIV-1 infection and is suppressed by the viral Vif protein | journal = Nature | volume = 418 | issue = 6898 | pages = 646–50 | date = Aug 2002 | pmid = 12167863 | doi = 10.1038/nature00939 | bibcode = 2002Natur.418..646S }}
* {{cite journal | vauthors = Huang X, Seifert U, Salzmann U, Henklein P, Preissner R, Henke W, Sijts AJ, Kloetzel PM, Dubiel W | title = 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 = Journal of Molecular Biology | volume = 323 | issue = 4 | pages = 771–82 | date = Nov 2002 | pmid = 12419264 | doi = 10.1016/S0022-2836(02)00998-1 }}
* {{cite journal | vauthors = Gaddis NC, Chertova E, Sheehy AM, Henderson LE, Malim MH | title = Comprehensive investigation of the molecular defect in vif-deficient human immunodeficiency virus type 1 virions | journal = Journal of Virology | volume = 77 | issue = 10 | pages = 5810–20 | date = May 2003 | pmid = 12719574 | pmc = 154025 | doi = 10.1128/JVI.77.10.5810-5820.2003 }}
* {{cite journal | vauthors = Lecossier D, Bouchonnet F, Clavel F, Hance AJ | title = Hypermutation of HIV-1 DNA in the absence of the Vif protein | journal = Science | volume = 300 | issue = 5622 | pages = 1112 | date = May 2003 | pmid = 12750511 | doi = 10.1126/science.1083338 }}
* {{cite journal | vauthors = Zhang H, Yang B, Pomerantz RJ, Zhang C, Arunachalam SC, Gao L | title = The cytidine deaminase CEM15 induces hypermutation in newly synthesized HIV-1 DNA | journal = Nature | volume = 424 | issue = 6944 | pages = 94–8 | date = Jul 2003 | pmid = 12808465 | pmc = 1350966 | doi = 10.1038/nature01707 | bibcode = 2003Natur.424...94Z }}
* {{cite journal | vauthors = Mangeat B, Turelli P, Caron G, Friedli M, Perrin L, Trono D | title = Broad antiretroviral defence by human APOBEC3G through lethal editing of nascent reverse transcripts | journal = Nature | volume = 424 | issue = 6944 | pages = 99–103 | date = Jul 2003 | pmid = 12808466 | doi = 10.1038/nature01709 | bibcode = 2003Natur.424...99M }}
* {{cite journal | vauthors = Harris RS, Bishop KN, Sheehy AM, Craig HM, Petersen-Mahrt SK, Watt IN, Neuberger MS, Malim MH | title = DNA deamination mediates innate immunity to retroviral infection | journal = Cell | volume = 113 | issue = 6 | pages = 803–9 | date = Jun 2003 | pmid = 12809610 | doi = 10.1016/S0092-8674(03)00423-9 }}
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* {{cite journal | vauthors = Gu Y, Sundquist WI | title = Good to CU | journal = Nature | volume = 424 | issue = 6944 | pages = 21–2 | date = Jul 2003 | pmid = 12840737 | doi = 10.1038/424021a | bibcode = 2003Natur.424...21G }}
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{{refend}}
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{{protein-stub}}
{{Proteasome subunits}}
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Revision as of 18:51, 7 September 2017

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26S proteasome non-ATPase regulatory subunit 1, also as known as 26S Proteasome Regulatory Subunit Rpn2 (systematic nomenclature), is a protein that in humans is encoded by the PSMD1 gene.[1][2] This protein is one of the 19 essential subunits that contributes to the complete assembly of 19S proteasome complex.[3]

Structure

Gene expression

The gene PSMD1 encodes the largest non-ATPase subunit of the 19S regulator base, which is responsible for substrate recognition and binding.[2] The human PSMD1 gene has 25 exons and locates at chromosome band 2q37.1. The human protein 26S proteasome non-ATPase regulatory subunit 1 is 106 kDa in size and composed of 953 amino acids. The calculated theoretical pI of this protein is 5.25. An alternative splicing during gene expression generates an isoform of the protein in which the amino acid sequence from 797-827 is missing.

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). Protein 26S proteasome non-ATPase regulatory subunit 1 (Rpn2) is an essential component of forming the base sub complex of 19S regulatory particle. Traditionally, Rpn1 and Rpn2 were considered residing at the center of base sub complex and surrounded by six AAA ATPases (Rpt 1-6). However, recent investigation provides an alternative structure of 19S base via an integrative approach combining data from cryoelectron microscopy, X-ray crystallography, residue-specific chemical cross-linking, and several proteomics techniques. Rpn2 is rigid protein located on the side of ATPase ring, supporting as the connection between the lid and base. Rpn1 is conformationally variable, positioned at the periphery of the ATPase ring. The ubiquitin receptors Rpn10 and Rpn13 are located further in the distal part of the 19S complex, indicating that they were recruited to the complex late during the assembly process.[4]

Function

As the degradation machinery that is responsible for ~70% of intracellular proteolysis,[5] 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. Rpn2 is the largest subunit of 19S regulatory particle and stays at the center of the "base" subcomplex of 19S particle.

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) [6] 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.[7] 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,[8][9] cardiovascular diseases,[10][11][12] inflammatory responses and autoimmune diseases,[13] and systemic DNA damage responses leading to malignancies.[14]

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,[15] Parkinson's disease[16] and Pick's disease,[17] Amyotrophic lateral sclerosis (ALS),[17] Huntington's disease,[16] Creutzfeldt–Jakob disease,[18] and motor neuron diseases, polyglutamine (PolyQ) diseases, Muscular dystrophies[19] and several rare forms of neurodegenerative diseases associated with dementia.[20] As part of the Ubiquitin-Proteasome System (UPS), the proteasome maintains cardiac protein homeostasis and thus plays a significant role in cardiac Ischemic injury,[21] ventricular hypertrophy[22] and Heart failure.[23] 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.[24] 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 selectine) and prostaglandins and nitric oxide (NO)[13] 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.[25] Lastly, autoimmune disease patients with SLE, Sjogren's syndrome and rheumatoid arthritis (RA) predominantly exhibit circulating proteasomes which can be applied as clinical biomarkers.[26]

A clinical study on patients with age related macula degeneration identified four significant proteins, including 26S proteasome non-ATPase regulatory subunit 1 (Rpn2), that were increased, according to semi-quantitative proteomic profiling. The study reported that an LC-MRM assay revealed a significant increase of Rpn2 in 15 macula degeneration patients compared to the control subjects, suggesting that this protein could be a biomarker for this condition.[27] Age-related macular degeneration is the leading cause of blindness in the world. Evidence is accumulating that the suppression of the UPS contributes to the increase of toxic proteins and inflammation in retina pigment epithelium, the functional abnormalities and/or the degeneration of which are believed to be the initiators and major pathologies of macula degeneration.[28] There are only limited options for the treatment of macular degeneration, thus early identification of susceptibility and preventive measures are important therapeutic strategies. New potential biomarkers for neovascular macular degeneratuon and UPS-related proteins that are altered in patients such as Rpn2 may serve as the basis for future clinical studies to determine target proteins involved in the protection of the eye against macula degeneration.[27][28]

References

  1. ↑ Yokota K, Kagawa S, Shimizu Y, Akioka H, Tsurumi C, Noda C, Fujimuro M, Yokosawa H, Fujiwara T, Takahashi E, Ohba M, Yamasaki M, DeMartino GN, Slaughter CA, Toh-e A, Tanaka K (Jun 1996). "CDNA cloning of p112, the largest regulatory subunit of the human 26s proteasome, and functional analysis of its yeast homologue, sen3p". Molecular Biology of the Cell. 7 (6): 853–70. doi:10.1091/mbc.7.6.853. PMC 275938. PMID 8816993.
  2. ↑ 2.0 2.1 "Entrez Gene: PSMD1 proteasome (prosome, macropain) 26S subunit, non-ATPase, 1".
  3. ↑ 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.
  4. ↑ Lasker K, Förster F, Bohn S, Walzthoeni T, Villa E, Unverdorben P, Beck F, Aebersold R, Sali A, Baumeister W (Jan 2012). "Molecular architecture of the 26S proteasome holocomplex determined by an integrative approach". Proceedings of the National Academy of Sciences of the United States of America. 109 (5): 1380–7. Bibcode:2012PNAS..109.1380L. doi:10.1073/pnas.1120559109. PMC 3277140. PMID 22307589.
  5. ↑ 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.
  6. ↑ Kleiger G, Mayor T (Jun 2014). "Perilous journey: a tour of the ubiquitin-proteasome system". Trends in Cell Biology. 24 (6): 352–9. doi:10.1016/j.tcb.2013.12.003. PMC 4037451. PMID 24457024.
  7. ↑ Goldberg AL, Stein R, Adams J (Aug 1995). "New insights into proteasome function: from archaebacteria to drug development". Chemistry & Biology. 2 (8): 503–8. doi:10.1016/1074-5521(95)90182-5. PMID 9383453.
  8. ↑ Sulistio YA, Heese K (Jan 2015). "The Ubiquitin-Proteasome System and Molecular Chaperone Deregulation in Alzheimer's Disease". Molecular Neurobiology. 53: 905–31. doi:10.1007/s12035-014-9063-4. PMID 25561438.
  9. ↑ Ortega Z, Lucas JJ (2014). "Ubiquitin-proteasome system involvement in Huntington's disease". Frontiers in Molecular Neuroscience. 7: 77. doi:10.3389/fnmol.2014.00077. PMC 4179678. PMID 25324717.
  10. ↑ Sandri M, Robbins J (Jun 2014). "Proteotoxicity: an underappreciated pathology in cardiac disease". Journal of Molecular and Cellular Cardiology. 71: 3–10. doi:10.1016/j.yjmcc.2013.12.015. PMC 4011959. PMID 24380730.
  11. ↑ Drews O, Taegtmeyer H (Dec 2014). "Targeting the ubiquitin-proteasome system in heart disease: the basis for new therapeutic strategies". Antioxidants & Redox Signaling. 21 (17): 2322–43. doi:10.1089/ars.2013.5823. PMC 4241867. PMID 25133688.
  12. ↑ Wang ZV, Hill JA (Feb 2015). "Protein quality control and metabolism: bidirectional control in the heart". Cell Metabolism. 21 (2): 215–26. doi:10.1016/j.cmet.2015.01.016. PMC 4317573. PMID 25651176.
  13. ↑ 13.0 13.1 Karin M, Delhase M (Feb 2000). "The I kappa B kinase (IKK) and NF-kappa B: key elements of proinflammatory signalling". Seminars in Immunology. 12 (1): 85–98. doi:10.1006/smim.2000.0210. PMID 10723801.
  14. ↑ Ermolaeva MA, Dakhovnik A, Schumacher B (Sep 2015). "Quality control mechanisms in cellular and systemic DNA damage responses". Ageing Research Reviews. 23 (Pt A): 3–11. doi:10.1016/j.arr.2014.12.009. PMC 4886828. PMID 25560147.
  15. ↑ Checler F, da Costa CA, Ancolio K, Chevallier N, Lopez-Perez E, Marambaud P (Jul 2000). "Role of the proteasome in Alzheimer's disease". Biochimica et Biophysica Acta. 1502 (1): 133–8. doi:10.1016/s0925-4439(00)00039-9. PMID 10899438.
  16. ↑ 16.0 16.1 Chung KK, Dawson VL, Dawson TM (Nov 2001). "The role of the ubiquitin-proteasomal pathway in Parkinson's disease and other neurodegenerative disorders". Trends in Neurosciences. 24 (11 Suppl): S7–14. doi:10.1016/s0166-2236(00)01998-6. PMID 11881748.
  17. ↑ 17.0 17.1 Ikeda K, Akiyama H, Arai T, Ueno H, Tsuchiya K, Kosaka K (Jul 2002). "Morphometrical reappraisal of motor neuron system of Pick's disease and amyotrophic lateral sclerosis with dementia". Acta Neuropathologica. 104 (1): 21–8. doi:10.1007/s00401-001-0513-5. PMID 12070660.
  18. ↑ Manaka H, Kato T, Kurita K, Katagiri T, Shikama Y, Kujirai K, Kawanami T, Suzuki Y, Nihei K, Sasaki H (May 1992). "Marked increase in cerebrospinal fluid ubiquitin in Creutzfeldt–Jakob disease". Neuroscience Letters. 139 (1): 47–9. doi:10.1016/0304-3940(92)90854-z. PMID 1328965.
  19. ↑ Mathews KD, Moore SA (Jan 2003). "Limb-girdle muscular dystrophy". Current Neurology and Neuroscience Reports. 3 (1): 78–85. doi:10.1007/s11910-003-0042-9. PMID 12507416.
  20. ↑ Mayer RJ (Mar 2003). "From neurodegeneration to neurohomeostasis: the role of ubiquitin". Drug News & Perspectives. 16 (2): 103–8. doi:10.1358/dnp.2003.16.2.829327. PMID 12792671.
  21. ↑ Calise J, Powell SR (Feb 2013). "The ubiquitin proteasome system and myocardial ischemia". American Journal of Physiology. Heart and Circulatory Physiology. 304 (3): H337–49. doi:10.1152/ajpheart.00604.2012. PMC 3774499. PMID 23220331.
  22. ↑ Predmore JM, Wang P, Davis F, Bartolone S, Westfall MV, Dyke DB, Pagani F, Powell SR, Day SM (Mar 2010). "Ubiquitin proteasome dysfunction in human hypertrophic and dilated cardiomyopathies". Circulation. 121 (8): 997–1004. doi:10.1161/CIRCULATIONAHA.109.904557. PMC 2857348. PMID 20159828.
  23. ↑ Powell SR (Jul 2006). "The ubiquitin-proteasome system in cardiac physiology and pathology". American Journal of Physiology. Heart and Circulatory Physiology. 291 (1): H1–H19. doi:10.1152/ajpheart.00062.2006. PMID 16501026.
  24. ↑ Adams J (Apr 2003). "Potential for proteasome inhibition in the treatment of cancer". Drug Discovery Today. 8 (7): 307–15. doi:10.1016/s1359-6446(03)02647-3. PMID 12654543.
  25. ↑ Ben-Neriah Y (Jan 2002). "Regulatory functions of ubiquitination in the immune system". Nature Immunology. 3 (1): 20–6. doi:10.1038/ni0102-20. PMID 11753406.
  26. ↑ Egerer K, Kuckelkorn U, Rudolph PE, Rückert JC, Dörner T, Burmester GR, Kloetzel PM, Feist E (Oct 2002). "Circulating proteasomes are markers of cell damage and immunologic activity in autoimmune diseases". The Journal of Rheumatology. 29 (10): 2045–52. PMID 12375310.
  27. ↑ 27.0 27.1 Lee H, Choi AJ, Kang GY, Park HS, Kim HC, Lim HJ, Chung H (May 2014). "Increased 26S proteasome non-ATPase regulatory subunit 1 in the aqueous humor of patients with age-related macular degeneration". BMB Reports. 47 (5): 292–7. doi:10.5483/bmbrep.2014.47.5.193. PMC 4163863. PMID 24286321.
  28. ↑ 28.0 28.1 Pickart CM (2001). "Mechanisms underlying ubiquitination". Annual Review of Biochemistry. 70: 503–33. doi:10.1146/annurev.biochem.70.1.503. PMID 11395416.

Further reading

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