PA-TM-RING tyyppinen RNF- alaperhe (9 jäsentä plus yksi poikkeusjäsen) Esimerkit (1) Goliat(RNF130) ja (2) GRAIL(RNF128)

PA-TM-RING alaperhe TM domeenin omaavissa RNF-proteiineissa

Se omaa kolme konservoitua domeenia: Proteaasiin liittynyt (PA) domeeni, transmembraani TM-domeeni ja RING-H2 finger- domeeni. Tässä alaperheessä on 9 jäsentä.Lisäksi yksi poikkeusjäsen, joka musituttaa edellisten C-terminaalipätkää.

(1) RNF130, Goliath,

(2) RNF128, Grail, Gene related to anergy in lymphocytes

(3) RNF133,

(4) RNF148, Grailin kaltainen domeeni  (HDAC säätelee tätä RNF148)

(5) RNF149, DNAPTP2, Grailin kaltainen domeeni

(6) RNF 150

(7) RNF 167

(8) RNF13

(9) RNF204, ZNRF4, Nixin, Sperizin, SPZN

useimmilla näistä on ilmeinen signaalipeptidisekvenssi N-terminaalissa, ei kutienkaan RNF204 joka on ZNRF4 , Nixin.

(10) RNF 122 on poikkeusjäsen PA-TM-RING-perheessä, koska siitä puuttuu signaalisekvenssin omaava alue ja PA-domaani.

PA-TM-RING proteiinit ovat ainutlaatuisia, koska niillä on extrasellulaarinen domeeni tai luminaalinen domeeni. Extrasellulaarinen tai luminaalinen domeeni löytyy myös useista reseptoreista ja peptidaaseista, joita on hiivalla, metazoilla ja kasveilla. Oletetaan PA-domeenin toimivan proteiini-proteiini-interaktiodomeenina. Todellakin GRAIL:in PA domeeni edistää proteiinisubstraatin tunnistamista ja siihen sitoutumista; esim CD154/CD40L tai CD83 ovat sen substraatteja.

RNF13 omistaa tumaan lokalisoivan signaalin (NLS) C-terminaalisessa alueessa joka sijaitsee TM-domeenin vierellä

• The PA-TM-RING family is defined by three conserved domains, the protease-associated (PA) domain,the transmembrane domain and the RING-H2 finger domain (Figure 3) [30,31]. The PA-TM-RING family is comprised of 9 proteins [Goliath/RNF130, gene related to anergy in lymphocytes (GRAIL)/RNF128, RNF133, RNF148, RNF149, RNF150, RNF167, RNF13 and zinc and ring finger 4 (ZNRF4)/Nixin/RNF204], and most of them possess apparent signal peptide sequences at their N-termini (Figure 3). RNF122 is an anomalistic member of the PA-TM-RING family, in that it lacks both the signal peptide sequence and PA domain. PA-TM-RING proteins are unique in containing an extracellular or luminal domain (Figure 3). The extracellular or luminal PA domain is also found in several receptors and peptidases in yeast, metazoans and plants [32]. The PA domain is proposed to serve as a protein–protein interaction module. Indeed, the PA domain of GRAIL facilitates the recognition of and binding to its substrate proteins (i.e., CD154/CD40L and CD83) [33,34]. RNF13 has a nuclear localization signal in the C-terminal region flanking the transmembrane domain [35].

(1) RNF130 (Kr.5 ) G1RZFP, GOLIATH, GP.  

Rakenne viittaa GRAIL-kaltaisiin ominaisuuksiin ( lymfosyyttianergiaan liittyvän geenin kaltainen  geeni . Tätä geeniä tiedettiin etsiä Drosophilageenin  ihmisvastineena, joten tämä kuuluu ns. uusiin havaittuihin geeneihin viime  vuosikymmeniltä.  hiireltäkin se löydettiin ensin. Se sääteli kasvutekijöiden puutteessa myeloisten  edeltäjäsolujen apoptoosia. Mola hydatidosan genitaustan tutkimuksissa   tämä geeni kuului  ylössäätyvien geenien ryhmään. Geeni ilmenee rasvakudoksessa, aivossa ja 25 muussa kudoksessa. Se on myös GRAIL-geenin paralogi ja ilmenee ihmisen  lymfosyyteissä. leukemisissa soluissa siitä ei kutienkaan ollut mitään ilmenemämuotoa tai modifikaatiota eikä se osallistunut solun erilaistumiseen eikä apoptoosiin.Tutkittaessa nomaaleja ja epäormaaleja luuydinnäytteitä, tätä geeniä ilmeni vain rajoittuneesti progeniittorien sytoplasmassa ja täysin erilaistuneissa leukosyyteissä.  

Kommenttini: ilmeisesti  tämä geeni GRAIL.in tapaan vastaa normaalista  anergiasta ja toleranssin kehittymisestä, siis siitä että ihminen syödessään ne 1000 kiloa kaikenlaista ruokaa vuodessa,  monta antigeenia mukana  vuoden aikana, ei reagoi ravinnolle lymfosyyteillään sairaalloisesti  joka ainut kerta,vaan  sietää ravintoproteiineja.  Tämä sieto on muuten alentunut keliakiassa  kotimaisia viljoja vastaan ja ehkä sieltä löytyy yhteyksi ätähän geeniryhmään. En ole löytänyt vielä suoraa yhteyttä näissä artikkelissa, mutta uutisia tulee toisaalta siitä, että  suolistotaudit  ja koliittit ovat väestössä lisääntymään päin) Siis normaali anergiajärjestelmä ja toleranssi  on järkkynyt.

• https://www.ncbi.nlm.nih.gov/gene/55819

• Also known as GP; G1RZFP; GOLIATH
• Summary The protein encoded by this gene contains a RING finger motif and is similar to g1, a Drosophila zinc-finger protein that is expressed in mesoderm and involved in embryonic development. The expression of the mouse counterpart was found to be upregulated in myeloblastic cells following IL3 deprivation, suggesting that this gene may regulate growth factor withdrawal-induced apoptosis of myeloid precursor cells. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2013]
• Expression Ubiquitous expression in fat (RPKM 11.3), brain (RPKM 9.7) and 25 other tissues See more
• Orthologs mouse all

Related articles in PubMed

1. Differential expression profiling of genes in a complete hydatidiform mole using cDNA microarray analysis. Kim SJ, et al. Gynecol Oncol, 2006 Nov. PMID 16797685
2. Goliath, a ring-H2 mitochondrial protein, regulated by luteinizing hormone/human chorionic gonadotropin in rat leydig cells. Guais A, et al. Biol Reprod, 2004 Jan. PMID 13679316
3. Cloning of murine G1RP, a novel gene related to Drosophila melanogaster g1. Baker SJ, et al. Gene, 2000 May 2. PMID 10806348
4. h-Goliath, paralog of GRAIL, is a new E3 ligase protein, expressed in human leukocytes. Guais A, et al. Gene, 2006 Jun 7. PMID 16549277 Abstract

• In Drosophila, the RING finger protein d-Goliath was originally identified as a transcription factor involved in the embryo mesoderm formation [Bouchard, M.L., Cote, S., 1993. The Drosophila melanogaster developmental gene g1 encodes a variant zinc-finger-motif protein. Gene 125, 205-209]. In mouse, the m-Goliath mRNA level was shown to be increased in growth factor withdrawal-induced apoptosis of myeloid cells [Baker, S.J., Reddy, E.P., 2000. Cloning of murine G1RP, a novel gene related to Drosophila melanogaster g1. Gene 248, 33-40]. Due to its putative function of transcription factor in apoptosis, we cloned the human cDNA for h-Goliath and characterized the expression of the protein in blood and bone marrow cells. The human protein of 419 aa (44 kDa) contains a protease-associated domain, a transmembrane domain and a RING-H2 motif. This structure classifies h-Goliath as a new member of a human family of ubiquitin ligases with GRAIL (gene related to anergy in lymphocytes) as founder. This E3 ligase controls the development of T cell clonal anergy by ubiquitination [Anandasabapathy, N., Ford, G.S., Bloom, D., Holness, C., Paragas, V., Seroogy, C., Skrenta, H., Hollenhorst, M., Fathman, C.G., Soares, L., 2003. GRAIL: an E3 ubiquitin ligase that inhibits cytokine gene transcription is expressed in anergic CD4+ T cells. Immunity 18, 535-547]. In vitro ubiquitination studies support the E3 ubiquitin ligase activity of h-Goliath. In human, the protein is expressed under 3 isoforms, a major one at 28 kDa and two others at 46 and 55 kDa. These proteins come from a common precursor (44 kDa) as we observed using in vitro transcription-translation. Using immunohistochemistry on blood or bone marrow smears, of healthy or leukemia samples, we found that the protein expression was restricted to the cytoplasm of progenitors and fully differentiated leukocyte populations. We did not observe any modification of h-Goliath expression or localization in leukemia. In these cells, this new E3 ubiquitin ligase protein does not seem associated with a differentiation state of the cell or with apoptosis.

5. Genome-wide association study of coronary heart disease and its risk factors in 8,090 African Americans: the NHLBI CARe Project. Lettre G, et al. PLoS Genet, 2011 Feb 10. PMID 21347282, Free PMC Article
   

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Peptide history, isoform 2 structure

https://www.ncbi.nlm.nih.gov/protein/NP_001267730.1

(2) RNF128 (Kr.Xq22.3), GRAIL,   Lymfosyyttianergiaan liittyvä geeni  Tämän PA-TM-RING RNF E3 ubikitiiniligaasien proteiiniryhmän perusjäsen.

SUOMENNOSTA tämän geenin vaikutuksesta:  Geenin koodaama proteiini on Tyypin I transmembraanin ja sijoittuu endosyyttiseen metaboliseen tiehen.

Tämä geeni ilmenee ohutsuolessa, maksassa ja 15 muusa kudoksessa, painotetusti suolistossa.   Tällä jotain tekemistä normaalin  suolistotoleranssin ( normaalin anergian) kanssa ja sen vikasäätelyä on suolistotaudeissa: haavainen paksunsuolentulehdus  ulceratiivinen koliitti ja Morbus Chron.  Auttaja-T-imusolujen , T-CD4(+) solujen kautta  se indusoi anergista fenotyyppiä.  Säätee T-CD 4(+) soluja  regulatiiviseen fenotyyppiseen muotoon. Tämän anergiaan assosioituneen geenin ylössäätyminen liittyy Notch-välitteiseen T-solujen suppressioon.  geeniä ilmenee ohustsuolessa, maksassa ja 15 muussa kudoksessa. GRAIL eli RNF128 ubikitinoi ja lähettää proteosomisilppuriin tetraspaniiniperheen jäseniä. geenin nimi GRAIl tulee sanoista Gene Related to Anergy In Lymphocytes proteins. Anergiaan assosioituva geeni imusolujen proteiineissa. 

https://www.ncbi.nlm.nih.gov/gene/79589

Also known as GRAIL. Summary

The protein encoded by this gene is a type I transmembrane protein that localizes to the endocytic pathway. This protein contains a RING zinc-finger motif and has been shown to possess E3 ubiquitin ligase activity. Expression of this gene in retrovirally transduced T cell hybridoma significantly inhibits activation-induced IL2 and IL4 cytokine production. Induced expression of this gene was observed in anergic CD4(+) T cells, which suggested a role in the induction of anergic phenotype. Alternatively spliced transcript variants encoding distinct isoforms have been reported. [provided by RefSeq, Jul 2008] Expression

Broad expression in small intestine (RPKM 27.8), liver (RPKM 27.8) and 15 other tissues See more Orthologs mouse all

Related articles in PubMed

1. Upregulation of GRAIL is associated with remission of ulcerative colitis. Egawa S, et al. Am J Physiol Gastrointest Liver Physiol, 2008 Jul. PMID 18467499
2. Regulation of anergy-related ubiquitin E3 ligase, GRAIL, in murine models of colitis and patients with Crohn's disease. Mukai A, et al. J Gastroenterol, 2014 Dec. PMID 24356810
3. Up-regulation of gene related to anergy in lymphocytes is associated with Notch-mediated human T cell suppression. Kostianovsky AM, et al. J Immunol, 2007 May 15. PMID 17475842
4. GRAIL is up-regulated in CD4+ CD25+ T regulatory cells and is sufficient for conversion of T cells to a regulatory phenotype. MacKenzie DA, et al. J Biol Chem, 2007 Mar 30. PMID 17259178
5. A novel E3 ubiquitin ligase substrate screen identifies Rho guanine dissociation inhibitor as a substrate of gene related to anergy in lymphocytes. Su L, et al. J Immunol, 2006 Dec 1. PMID 17114425
   

See all (22) citations in PubMed
See citations in PubMed for homologs of this gene provided by HomoloGene

GeneRIFs: Gene References Into FunctionsWhat's a GeneRIF?

1. results show that expression of GRAIL is uniquely regulated by the specific miRNA in intestinal mucosa, and suggest that GRAIL may associate with the pathophysiology of Crohn's disease
2. study shows that Grail has a novel, p53-dependent role in regulating the cell cycle and apoptosis
3. GRAIL can down-modulate the expression of CD83 antigen on CD4 T cells.
4. endogenous GRAIL regulates general cell cycle and proliferation of primary naive CD4 T cells.
   Suomennosta: GRAIL eli RNF128  vaikuttaa täysin kypsille  dendriittisoluille tarkoitetun   pintareseptorin CD83 (klusteritekijän) alassäätymisen   ja voi lähettää  intaktin  CD83 reseptorin proteosomiin. jolloin TCD4(+) solut ovat  anergioistuneinä kuten lepotilassakin. Jos RNA interferenssi poistaa GRAIL-vaikutuksen T-solusta, CD83 pitoisuus nousee ja osaltaan vaikuttaa T-soluaktiivisuutta  ko-stimulatorisena molekyylinä. 
   • Ubiquitination of eukaryotic proteins regulates a broad range of cellular processes, including T cell activation and tolerance. We have previously demonstrated that GRAIL (gene related to anergy in lymphocytes), a transmembrane RING finger ubiquitin E3 ligase, initially described as induced during the induction of CD4 T cell anergy, is also expressed in resting CD4 T cells. In this study, we show that GRAIL can down-modulate the expression of CD83 (previously described as a cell surface marker for mature dendritic cells) on CD4 T cells. GRAIL-mediated down-modulation of CD83 is dependent on an intact GRAIL extracellular protease-associated domain and an enzymatically active cytosolic RING domain, and proceeds via the ubiquitin-dependent 26S proteosome pathway. Ubiquitin modification of lysine residues K168 and K183, but not K192, in the cytoplasmic domain of CD83 was shown to be necessary for GRAIL-mediated degradation of CD83. Reduced CD83 surface expression levels were seen both on anergized CD4 T cells and following GRAIL expression by retroviral transduction, whereas GRAIL knock-down by RNA interference in CD4 T cells resulted in elevated CD83 levels. Furthermore, CD83 expression on CD4 T cells contributes to T cell activation as a costimulatory molecule. This study supports the novel mechanism of ubiquitination by GRAIL, identifies CD83 as a substrate of GRAIL, and ascribes a role for CD83 in CD4 T cell activation. 
5. GRAIL captures and then ubiquitinates transmembrane proteins across the cell membrane
   Suom. GRAIL ubikitinoi ja hajoittaa tetraspaniiniperheen jäseniä
6. GRAIL expression was significantly higher in patients with ulcerative colitis in remission than in patients with active disease and in healthy volunteers.
7. Inhibition of T cell activation is not due to apoptosis or disruption of proximal T- cell receptor signaling, but is associated with up-regulation of GRAIL in CD4+ T cells, with modest effects on other E3 ubiquitin ligases.
8. Forced expression of GRAIL in a T cell line from a T-cell receptor transgenic mouse is sufficient for conversion of these cells to a regulatory phenotype.
   

 GRAIL (gene related to anergy in lymphocytes) is an ubiquitin-protein isopeptide ligase (E3) ubiquitin ligase necessary for the induction of CD4(+) T cell anergy in vivo. We have extended our previous studies to characterize the expression pattern of GRAIL in other murine CD4(+) T cell types with a described anergic phenotype. These studies revealed that GRAIL expression is increased in naturally occurring (thymically derived) CD4(+) CD25(+) T regulatory cells (mRNA levels 10-fold higher than naive CD25(-) T cells). Further investigation demonstrated that CD25(+) Foxp3(+) antigen-specific T cells were induced after a "tolerizing-administration" of antigen and that GRAIL expression correlated with the CD25(+) Foxp3(+) antigen-specific subset. Lastly, using retroviral transduction, we demonstrated that forced expression of GRAIL in a T cell line was sufficient for conversion of these cells to a regulatory phenotype in the absence of detectable Foxp3. These data demonstrate that GRAIL is differentially expressed in naturally occurring and peripherally induced CD25(+) T regulatory cells and that the expression of GRAIL is linked to their functional regulatory activity.

Submit: New GeneRIF Correction

Peptide history and one isoform structure

https://www.ncbi.nlm.nih.gov/protein/NP_078815.3