konventionelleistä ja ei-konventionelleistä:
Konventionellit: UBA1, UBA6, UBA7 jotka ovat monomeerejä,
SAE1 ja UBA2 , jotka esiintyvät heterodimeerinä
NAE1 ja UBA3 jotka esiintyvät heterodimeerinä .
Ei-konventionellejä:
UBA4/MOCS53m joka esiintyy homodimeerinä.
UBA5 joka esiintyy homodimeerinä
ja ATG7, joka esiintyy homodimeerinä.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2712597/
Nat Rev Mol Cell Biol. Author manuscript; available in PMC 2009 Nov 1.
Published in final edited form as:
Ubiquitin-like protein activation by E1 enzymes: the apex for downstream signalling pathways
A major mechanism for regulating protein function in
eukaryotes involves covalent attachment of ubiquitin or ubiquitin-like
proteins (referred to collectively as UBLs) to the primary amino group
of a target, often from a Lys side-chain, through an isopeptide bond.
Post-translational modification by UBLs regulates numerous processes,
which include cell division, immune responses and embryonic development.
Accordingly, defects in UBL pathways are associated with various
diseases, particularly cancer, neurodegenerative disorders, and muscle
atrophy or ‘cachexia’1,2.
The
UBL carboxyl termini are attached to other proteins, or in some cases
lipids, generally through E1-E2-E3 multienzyme cascades (FIG. 1a).
- At the apex of each UBL cascade is an E1 enzyme, which activates the UBL and then directs the UBL to downstream pathways (FIG. 1).
E1 domain structures and enzymatic mechanism
a | Primary structures of human canonical and noncanoncal E1 enzymes, with domains indicated and coloured according to the legend (bottom), and adenylation domains aligned according to molybdopterin biosynthetic enzyme B (MoeB) and thiamine biosynthesis enzyme F (ThiF) primary structures shown above. Lines reflect insertions in sequences between conserved domains. b | Cartoon view of canonical E1 crystal structures with ubiquitin (yellow) associated noncovalently at the adenylation active site of Saccharomyces cerevisiae Uba1 (3CMM.PDB)51, c | with small ubiquitin-related modifier (SUMO)- 1 (yellow) and ATP associated noncovalently at the adenylation active site of SAE1-UBA2 (1Y8R.PDB)50, and d | with NEDD8 (yellow) and ATP noncovalently at the adenylation active site of NAE1-UBA3 (1R4M.PDB)67. The domains are coloured according to the schematic view in panel a, and oriented as the left view of MoeB in FIG. 2a.
( Koommentti : Tässä linkissä on valaiseva kuva ihmisen E1- entsyymien domeenien kaavasta!)
" The ubiquitin system itself is the best understood UBL pathway. In the
first step of ubiquitin activation, the E1 enzyme binds MgATP and
ubiquitin, and catalyzes ubiquitin C-terminal acyl-adenylation.
In the
second step, the catalytic Cys in the E1 attacks the ubiquitin~adenylate
to form the activated ubiquitin~E1 complex (the tilde “~” represents a
high-energy thioester bond between the C-terminal carboxylate of the
ubiquitin-like protein and the conjugation machinery or AMP, while a
dash “-” represents a non-covalent complex).
Ultimately, an E1 engages
one of up to tens of cognate E2 conjugating enzymes to initiate
downstream signalling, typically through the coordinated function of E3
ubiquitin ligases (FIG. 1). E3s contain binding sites for both charged E2s and ubiquitylation substrates3.
For the largest class of E3s (the Really Interesting New Gene, RING,
and the RING-related U-box family), an ε-amino group of a Lys residue in
the associated substrate attacks the thioester of the transiently
associated charged E2 to make an isopeptide bond with ubiquitin. The
discharged E2 then dissociates from the E3, allowing a second charged E2
to interact with the E3, facilitating a second round of ubiquitin
transfer, either by attack of a Lys residue in ubiquitin itself or by
attack of a different Lys in the substrate. Multiple E2 cycles of
E1-mediated ubiquitin loading and subsequent unloading – through a
variety of mechanisms (reviewed in 4) - lead to polyubiquitylation of the substrate (FIG. 1a, b)."
(2018 kirjoitin muistiin seuraavia geenejä, vasemmassa rivissä E1 entsyymit )
(1)
https://kops.uni-konstanz.de/bitstream/handle/123456789/1200/Groettrup_opus-85098.pdf?sequence=1
Netistä löytyy luetteloita ubikitiinin (Ub) ja sen kaltaisten (Ubl) modifioivien molekyylien aktivoivasta entsyymistä.
Tässä luettelossa mainitaan vuonna 2008. Mainitaan myös Ub/Ubl- molekyyli, jonka entsyymi E1 aktivoi ja sitten myös vastaava konjugaasi (E2) , joka ottaa kuljetettavakseen Ub/Ubl
E1. entsyymi Ub(Ubl E2 entsyymi
- UBE1 (ULM: Ub ), (E2: usea E2)
- UBE1L (ULM: ISG15), ( E2 UbcH8)
- AOS (SAE1) (ULM: SUMO-1,-2,-3); ( E2: UBC9)
- UBA2 (SAE2) (ULM: (E2: UBC12)
- APP-BP-1 (ULM: NEDD8) , (E2: UBC12)
- UBA3
- UBA4 (MOC53) (URM-1), (Unknown)
- UBA5 (UBE TDC1) (Ubiquitin) (Ufc1)
- UBAC (UBE1L2), E1-L2) (Ub , FAT10) (Unknown)
- ATG7 (ATG12, ATG8) (ATg10, atg3)
(2) Minkälaisen luettelon antaa Wikipedia?
- https://en.wikipedia.org/wiki/Ubiquitin-activating_enzyme
- Ubiquitin-activating enzymes, also known as E1 enzymes, catalyze the first step in the ubiquitination reaction, which (among other things) can target a protein for degradation via a proteasome. This covalent attachment of ubiquitin (Ub) or ubiquitin-like (Ubl) proteins to targeted proteins is a major mechanism for regulating protein function in eukaryotic organisms.[2] Many processes such as cell division, immune responses and embryonic development are also regulated by post-translational modification by ubiquitin and ubiquitin-like proteins.[2]
The following human genes encode ubiquitin-activating enzymes:
Tästä huomaa, että molemmissä artikkeleissa kirjoittajilla on käytössä eri synonyymit.
Sen takia katson PubMed lähteessä kaikki käytetyt synonyymit geenille joka proteiinia koodaa ja samalla sen nimen jonka tiedemiehet asettavat ensisijalle
- (3) PubMed lähteestä tarkistan luettelon ja teen synteesin synonyymeistä alla tässä tarkemmin puuttumatta entsyymiominaisuuksiin . Kaikki kuitenkin suorittavat Ub / Ubl aktivointia
UBA1, (X 11.3) ubiquitin like modifier activating enzyme 1
https://www.ncbi.nlm.nih.gov/gene/7317
Synonyymejä: UBE1, A159, A159T, A1ST, AMCX1, CFAP124, GXP1, POC20, SMAR2A, UBE1X, UBA1A
Päivits : UBA1:een kohdistuva pienimolekulaarinen lääkeaine on kliinisessä kokeilussa TAK-243 ja se tehostaa KAFTRIO- lääkekombinaation vaikutusta kystisen fibroosin oireiden vähentämisessä.
. 2022 Mar 16;79(4):192.
doi: 10.1007/s00018-022-04215-3.
Targeting the E1 ubiquitin-activating enzyme (UBA1) improves
elexacaftor/tezacaftor/ivacaftor efficacy towards F508del and rare
misfolded CFTR mutants
Affiliations
UBA2, ( 19q13.32 ) ubiquitin like modifier activating enzyme 2
https://www.ncbi.nlm.nih.gov/gene/10054Synonyymejä: ARX, HRIHFB2115, SAE2*
UBA3, (3p14.1), ubiquitin like modifier activating enzyme 3
Synonyymejä: NAE2, UBE1C, hUBA3,https://www.ncbi.nlm.nih.gov/gene/9039 ( Tämä nettiosoite ei toimi. Hae: UBA3 nimellä)
UBA4, (20q13.13), MOCS3, molybdenum cofactor synthesis 3
https://www.ncbi.nlm.nih.gov/gene/27304Synonym UBA4, Preferred name MOCS.
(Suom: Tämä on molybdocofaktori, jota kaikki molybdeenientsyyymit välttämättä tarvitsevat).
Rakenteessa E1 domeeni ja Rhodaneesi-domeeni . Kts. linkki.
tRNA:lle tärkeä tiolaatio
The Uba4 domain interplay is mediated via a thioester that is critical for tRNA thiolation through Urm1 thiocarboxylation
Nucleic Acids Research, Volume 46, Issue 10, 1 June 2018, Pages 5171–5181, https://doi.org/10.1093/nar/gky312
30 April 2018
Article history
UBA5, (3q22.1), (Ubiquitin fold modifier-1 activator )
https://www.ncbi.nlm.nih.gov/gene/79876
Synonyymit: EIEE44; SCAR24; THIFP1; UBE1DC1.
UBA6, (4q13.3), ubiquitin like modifier activating enzyme67
https://www.ncbi.nlm.nih.gov/gene/55236
Synonyms E1-L2, MOP-4, UBE1L2 .
UBA7, (3p21.38), ubiquitin like modifier activating enzyme 7
https://www.ncbi.nlm.nih.gov/gene/7318
Synonyms D8, UBA1B, UBE1L, UBE2.
ATG7 (3p25.3) Autophagy related 7
https://www.ncbi.nlm.nih.gov/gene/10533
APG7-like, APG7L,GSA7.
NAE1 (16q22.1) NEDD8 activating enzyme E1 subunit 1
https://www.ncbi.nlm.nih.gov/gene/8883Synonyms: APPBP1, HPP1, A-11610.1, ula-1.
SAE1 (19q13.32) SUMO1 activating enzyme subunit 1
https://www.ncbi.nlm.nih.gov/gene/10055Synonyms: AOS1; SUA1; UBLE1A; HSPC140.
*(SAE1 and UBA2(SAE2*) forms heterodimer and work together as SUMO activating enzyme)
( There can be more modifiers and more E1 activators).
24.6. 2019 Lukiessani ferritiiniä säätelevistä proteiineista ja niisien degradaatiosta, tapaan maininnan ATG5.stä
ATG5 (6q21)
https://www.ncbi.nlm.nih.gov/gene/9474
Also known as ASP; APG5; APG5L; hAPG5; SCAR25; APG5-LIKE Summary The protein encoded by this gene, in combination with autophagy protein 12, functions as an E1-like activating enzyme in a ubiquitin-like conjugating system. The encoded protein is involved in several cellular processes, including autophagic vesicle formation, mitochondrial quality control after oxidative damage, negative regulation of the innate antiviral immune response, lymphocyte development and proliferation, MHC II antigen presentation, adipocyte differentiation, and apoptosis. Several transcript variants encoding different protein isoforms have been found for this gene. [provided by RefSeq, Sep 2015] Expression Ubiquitous expression in thyroid (RPKM 11.9), adrenal (RPKM 11.0) and 25 other tissues See more Orthologs mouse all
Preferred Names: autophagy protein 5 , (ATG5).
- Names
- APG5 autophagy 5-like ,(APG5-L)
- ATG5 autophagy related 5 homolog
- apoptosis-specific protein, (ASP)
ATG5 regulates histone H2B mono-ubiquitylation by translational control of RNF20 -
- Features: NP_001273035.1 autophagy protein 5 isoform a
- Conserved Domains (1) summary pfam04106
- Location:79 → 270 APG5; Autophagy protein Apg5
- APG5 konjugoituu APG12:n kanssa ja yhdessä ne toimivat E1 ub. ligaasijärjestelmässä.
- ATG12 on autofagosomin muodostuksesa kriittinen geeni.
- APG12(5q22.3)
- https://www.ncbi.nlm.nih.gov/gene/9140 Preferred Names
- ubiquitin-like protein ATG12
- Names
- APG12 autophagy 12-like
- ATG12 autophagy related 12 homolog
- Apg12 (autophagy, yeast) homolog
- ATG12 expression quantitative trait loci associated with head and neck squamous cell carcinoma risk in a Chinese Han population. Song X, et al. Mol Carcinog, 2018 Aug. PMID 29637616
- Novel and functional ATG12 gene variants in sporadic Parkinson's disease. Li Y, et al. Neurosci Lett, 2017 Mar 16. PMID 28229934. Parkinson's disease (PD) is a common and progressive neurodegenerative disease, including familial and sporadic cases. To date, genetic causes for sporadic PD, majority of PD cases, remain largely unknown. Accumulating evidence indicates that dysfunctional autophagy, a highly conserved cellular process, is involved in the PD pathogenesis. We speculated that changed expression levels of autophagy-related genes (ATG) may contribute to PD development. Previously, we have genetically analyzed ATG5 and ATG7 genes in sporadic PD patients and identified several functional DNA sequence variants (DSVs). In groups of sporadic PD patients and ethic-matched healthy controls in this study, we further genetically and functionally analyzed the promoter of ATG12, a critical gene for autophagososme formation. The results showed that three DNA sequence variants (DSVs), g.115842507G>T, g.115842394C>T and g.115841817_18del, were identified three PD patients, which significantly altered transcriptional activity of ATG12 gene promoter, probably due to abolishing or creating binding sites for transcription factors. The transcriptional activity of ATG12 gene promoter was not significantly affected by other two DSVs identified in PD patients, g.115842640A>C and g.115842242G>C, which may not alter binding sites for transcription factors. Therefore, these three functional DSVs identified in PD patient may change ATG12 protein levels, contributing to PD development as a risk factor by interfering with autophagy as well as non-autophagy functions.
- Ubiquitination and proteasomal degradation of ATG12 regulates its proapoptotic activity. Haller M, et al. Autophagy, 2014. PMID 25629932, Free PMC Article During macroautophagy, conjugation of ATG12 to ATG5 is essential for LC3 lipidation and autophagosome formation. Additionally, ATG12 has ATG5-independent functions in diverse processes including mitochondrial fusion and mitochondrial-dependent apoptosis. In this study, we investigated the regulation of free ATG12. In stark contrast to the stable ATG12-ATG5 conjugate, we find that free ATG12 is highly unstable and rapidly degraded in a proteasome-dependent manner. Surprisingly, ATG12, itself a ubiquitin-like protein, is directly ubiquitinated and this promotes its proteasomal degradation. As a functional consequence of its turnover, accumulation of free ATG12 contributes to proteasome inhibitor-mediated apoptosis, a finding that may be clinically important given the use of proteasome inhibitors as anticancer agents. Collectively, our results reveal a novel interconnection between autophagy, proteasome activity, and cell death mediated by the ubiquitin-like properties of ATG12.
- Mitochondrial DNA deletions and chloramphenicol treatment stimulate the autophagic transcript ATG12. Prigione A, et al. Autophagy, 2007 Jul-Aug. PMID 17457038
- Ambra1 modulates the sensitivity of breast cancer cells to epirubicin by regulating autophagy via ATG12. Sun WL, et al. Cancer Sci, 2018 Oct. PMID 30027574, Free PMC Article
- These results suggested that ATG12 expression quantitative trait loci SNP rs26537 might contribute to an allele-specific effect on the expression of host gene ATG12 and explain a fraction of head and neck squamous cell carcinoma genetic susceptibility.
- this study identified a novel mechanism by which oncogenic RAS promotes survival of malignant intestinal epithelial cells. This mechanism is driven by RAS-dependent loss of ATG12 in these cells.
- miR-23a downregulation modulates the inflammatory response by targeting ATG12-mediated autophagy.
- the role of the autophagy elongation complex (ATG5-12/16L1) in Hepatitis C virus replication and membranous web formation, was examined.
- Ambra1 plays an important role in regulating the sensitivity of breast cancer cells to epirubicin. Regulatory effect of Ambra1 on epirubicin sensitivity is achieved through the regulation of autophagy by targeting ATG12.
- The finding that miR378 targets ATG12 indicated that miR378 may have a potential role in autophagy. These findings may provide novel insights into the mechanism of metastasis in cervical cancer and a novel therapeutic target for the treatment of cervical cancer.
- Results show that ATG12 is a downstream effector in MALAT1-mediated autophagy in gastric cancer cells.
- HBV gained access to Atg5-12/16L1 via interaction of its core protein with the Atg12 moiety of the complex. In contrast, subsequent autophagosome maturation and closure events were unnecessary for HBV replication, as evidenced by inhibition of Atg8/LC3 conjugation. Interfering with the HBV/Atg12 cross talk may be a tool for virus control.
- transcriptional activity of ATG12 gene promoter was not significantly affected by other two DNA sequence variants identified in Parkinson's disease patient
- STAT3 and ATG12 are targets of miR-454-3p.
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