Otan tässä tuosta kyposästä sarjasta nsp6-proteiinin.
Se sijaitsee replikaasin kohdassa 3570-3859 ja on 290 aminohappoa pitkä. Se toimii ankkurina muille non-struktureille proteiineille muodsotettaessa replikaatio-transkriptio-kompleksia RTC.
Nsp6 on kalvorakenteita modifioiva ja osallistuu kalvorakkuloiden muodostamiseen ja autofagosomin indusoimiseen. Se on aivan esentielli tekijä COV-virukselle. Nsp6:n saa muodostumaan yksinkertaisten kalvojen, ja yhdessä nsp3:n ja nsp4:n kanssa muodostuu retikulovesikulaarinen verkosto pariutuneita, lähekkäin ja vastakkain olevia kalvoja, joissa on myös tavallisten rakkuloiden lisäksi kaksoiskerroksellisia rakkuloita ( Double Membrane Vesicles, DMV) ja rakkulapaketteja (Vesicle Packets (VPS) ja ne kaikki ovat yhteydessä endoplasmiseen verkostoon(ER) ulokokalvonsa välityksellä. VPS- rakkulapaketit sisältävät multippeleja sisärakkuloiita ja silmukoitumia ja lopulta myös täysin koostuja virioneita VP- rakkulapaketti saataa olla muodostunut kaksoikalvorakkulan laajentumasta. Näissä suojatuissa kalvoissa siten voi piillä virusgenomin vaurioalttein vaihe dsRNA-muoto, jonka havaitsemiseen sytoplasmassa olisi monta sensoria, mtua näistä piilopaikoista dsRNA-muoto ei tunnistu.
Koronavirus onkin varustanut työkaluihinsa usemman tekijän , jotka saavat yhdessä aikaan lipidien modifioinnin. Ilman lipidien antamaa suojaa, sen replikoituminen ei onnistuisi nopeasti.
Lipidien merkitys on jo aiemmin havaittu: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6357182/
SARS-2-CoV nsp6: Struktuurista Sveitsin mallin mukaan
Non-structural protein 6
Plays a role in the initial induction of autophagosomes from host reticulum endoplasmic. Later, limits the expansion of these phagosomes that are no longer able to deliver viral components to lysosomes Only remote homologues were identified as potential template structures, limiting the expected quality of the models.
See here for available low quality models.
Sequence identity 10,26 %: CALBINDIN
Sequence identity 18,53%: mitochondrial,NADH dehydrogenase [ubiquinone] 1 beta subcomplex subunit 5. ( Complex I)
https://swissmodel.expasy.org/templates/5lc5.1
SARS-2CoV nsp6 interaktioproteiinit ihmisen proteiinien kanssa: ATP13A3; ATP6AP1; ATP5MG; SIGMAR1 (PubMed haku näistä 4 geeneistä). Ne vaikuttavat muokkaavaan miljöön happo-emäs-tasapainoasioita ja jonipitoisuuksia sekä energiaolosuhteita solunsisäisissä kalvo-organelleissa ja mitokondriassa.
LÄHTEESTÄ https://www.biorxiv.org/content/10.1101/2020.03.22.002386v1.full.pdf
.CC-BY 4.0 International license(which was not certified by peer review) is the author/funder. It is made available under aThe copyright holder for this preprintthis version posted March 22, 2020. . https://doi.org/10.1101/2020.03.22.002386doi
ATP13A3 (3q29), AFURS1.
https://www.ncbi.nlm.nih.gov/gene/79572
ATP13A3. Official Full Name; ATPase 13A3. Also known as AFURS1.
Summary: ATP13A3 is a member of the P-type ATPase family of proteins that transport a variety of cations across membranes. Other P-type ATPases include ATP7B (MIM 606882) and ATP7A (MIM 300011).[supplied by OMIM, Aug 2008] Expression Ubiquitous expression in thyroid (RPKM 24.7), appendix (RPKM 18.3) and 25 other tissues See more.
Preferred Names: probable cation-transporting ATPase 13A3.
Names: ATPase family homolog up-regulated in senescence cells 1.
ATPase type 13A3.
FEATURES: NP_078800.3 probable cation-transporting ATPase 13A3 isoform 1
Conserved Domains (6) summary
- TIGR01657
Location:14 → 1149 - P-ATPase-V; P-type ATPase of unknown pump specificity (type V).These P-type ATPases form a distinct clade but the substrate of their pumping activity has yet to be determined. This clade has been designated type V in.
- pfam00122
Location:236 → 483. E1-E2_ATPase; E1-E2 ATPase, alayksikkö
- pfam00690
Location:178 → 226. Cation_ATPase_N; Cation transporter/ATPase, N-terminus
- pfam12409
Location:13 → 145. P5-ATPase; P5-type ATPase cation transporter - This domain family is found in eukaryotes, and is typically between 110 and 126 amino acids in length. The family is found in association with pfam00122, pfam00702. P-type ATPases comprise a large superfamily of proteins, present in both prokaryotes and eukaryotes, that transport inorganic cations and other substrates across cell membranes.
- pfam13246
Location:622 → 662. Cation_ATPase; Cation transport ATPase (P-type). This domain is found in cation transport ATPases, including phospholipid-transporting ATPases, calcium-transporting ATPases, and sodium-potassium ATPases.
- cl21460
Location:821 → 898 HAD_like; Haloacid Dehalogenase-like Hydrolases
Haloacid Dehalogenase-like HydrolasesThe haloacid dehalogenase (HAD) superfamily includes carbon and phosphorus hydrolases such as 2-haloalkonoate dehalogenase, epoxide hydrolase, phosphoserine phosphatase, phosphomannomutase, phosphoglycolate phosphatase, P-type ATPase, among others. These proteins catalyze nucleophilic substitution reactions at phosphorus or carbon centers, using a conserved Asp carboxylate in covalent catalysis. All members possess a conserve alpha/beta core domain, and many also possess a small cap domain, with varying folds and functions.
ATP6AP1 (Xq28) , VATPS1
Solunsisäisten organellien happamuuden muodostaja, vakuolaarinen ATPaasi (V-ATPaasi).Omaa sytosolisen V1-domeenin ja rakkulan puoleisen V0-domeenin. Omaa merkitystä proteiinien lajittelussa, zymogeenien aktivoimisessa ja reseptorivälitteisessä endosytoosissa. Ilmentyy aivoissa, kilpirauhasessa ja 25 muussa kudoksessa.
Valaiseva artikkeli, jossa on kuva: https://www.sciencedirect.com/science/article/pii/S0005272814000280
https://www.ncbi.nlm.nih.gov/gene/537
ATP6AP1. Official Full Name. ATPase H+ transporting accessory protein 1.Also known as 16A; CF2; Ac45; XAP3; XAP-3; ATP6S1; VATPS1; ATP6IP1Summary. This gene encodes a component of a multisubunit enzyme that mediates acidification of eukaryotic intracellular organelles. Vacuolar ATPase (V-ATPase) is comprised of a cytosolic V1 domain (site of the ATP catalytic site) and a transmembrane V0 domain. V-ATPase dependent organelle acidification is necessary for such intracellular processes as protein sorting, zymogen activation, and receptor-mediated endocytosis. The encoded protein of this gene may assist in the V-ATPase-mediated acidification of neuroendocrine secretory granules. This protein may also play a role in early development. [provided by RefSeq, Aug 2013]Expression: Ubiquitous expression in brain (RPKM 59.1), thyroid (RPKM 48.0) and 25 other tissues See more.
Preferred Names:V-type proton ATPase subunit S1
Names::ATPase, H+ transporting, lysosomal (vacuolar proton pump), subunit 1.
ATPase, H+ transporting, lysosomal accessory protein 1,
ATPase, H+ transporting, lysosomal interacting protein 1,
H-ATPase subunit,
V-ATPase Ac45 subunit,
V-ATPase S1 accessory protein,
V-ATPase subunit S1,
epididymis secretory sperm binding protein,
protein XAP-3,
vacuolar proton pump subunit S1.
FEATURES:
NP_001174.2 V-type proton ATPase subunit S1 precursor.
- Conserved Domains (1) summary
-
- pfam05827
Location:321 → 468 - ATP-synt_S1; Vacuolar ATP synthase subunit S1 (ATP6S1)
- pfam05827
Novel insights into V-ATPase functioning: distinct roles for its accessory subunits ATP6AP1/Ac45 and ATP6AP2/(pro) renin receptor. Jansen EJ1, Martens GJ. Abstract
The
vacuolar (H+)-ATPase (V-ATPase) is a universal proton pump and its
activity is required for a variety of cell-biological processes such as
membrane trafficking, receptor-mediated endocytosis, lysosomal protein
degradation, osteoclastic bone resorption and maintenance of acid-base
homeostasis by renal intercalated cells. In neuronal and neuroendocrine
cells, the V-ATPase is the major regulator of intragranular
acidification which is indispensable for correct prohormone processing
and neurotransmitter uptake. In these specialized cells, the V-ATPase is
equipped with the accessory subunits ATP6AP1/Ac45 and ATP6AP2/(pro)
renin receptor. Recent studies have shown that Ac45 interacts with the
V0- sector of the V-ATPase complex, thereby regulating the intragranular
pH and Ca2+-dependent exocytotic membrane fusion. Thus, Ac45 can be
considered as a V-ATPase regulator in the neuroendocrine secretory
pathway. ATP6AP2 has recently been found to be identical to the (pro)
renin receptor and has a dual role: (i) in the renin-angiotensin system
that also regulates V-ATPase activity; (ii) acting as an adapter by
binding to both the V-ATPase and the Wnt receptor complex, thereby
recruiting the receptor complex into an acidic microenvironment. We here
provide an overview of the two V-ATPase accessory subunits as novel key
players in V-ATPase regulation. We argue that the accessory subunits
are candidate genes for V-ATPase-related human disorders and promising
targets for manipulating V-ATPase functioning in vivo.
| Genome-wide shRNA screening identifies ATP6AP1, which is required for HIV-1 Nef-induced downregulation of CD4 in HeLa CD4+ cells. |
ATP5MG (11q23.3), Mitochondrial ATP synthase, subunit g
ATPMG katalysoi ATP-energia-pakettien muodostumista hyödyntäen protonien (H+) suomaa elektrokemiallista gradienttia, joka vallitsee mitokondrian sisäkalvon molemmin puolin oksidatiivisen fosforylaation aikana.
Kuva havainnollistaa ATP-energiapakettien synteesikoneistoa : https://www.sigmaaldrich.com/life-science/metabolomics/learning-center/metabolic-pathways/atp-synthase.html
ATP5MG proeiini muodostuu kahdesta linkkiytyneestä monialayksikköisestä kompleksista. Toinen on liukoinen katalyyttinen ydin F1 ja toinen on kalvoon asettunut komponentti F0.
F1-komponentti koostuu on viidestä erilaisesta alayksikkötyypistä (alfa, beeta, gamma, delta ja epsilon) järjestäytyneenä suhteeessa 3 alfaa, 3 beetaa ja muita on yksi kutakin.
F0- komponentti omaa yhdeksän alayksikköä ( a,b,c,d,e,f,g,F6 ja 8) .
Tämä geeni koodaa alayksikön g. kalvossa siajitsevassa F0-komponentissa.
https://www.ncbi.nlm.nih.gov/gene/10632
Official Symbol ATP5MG.Also known as ATP5L; ATP5JG
Summary: Mitochondrial ATP synthase catalyzes ATP synthesis, utilizing an electrochemical gradient of protons across the inner membrane during oxidative phosphorylation. It is composed of two linked multi-subunit complexes: the soluble catalytic core, F1, and the membrane-spanning component, Fo, which comprises the proton channel. The F1 complex consists of 5 different subunits (alpha, beta, gamma, delta, and epsilon) assembled in a ratio of 3 alpha, 3 beta, and a single representative of the other 3. The Fo seems to have nine subunits (a, b, c, d, e, f, g, F6 and 8). This gene encodes the g subunit of the Fo complex. Alternative splicing results in multiple transcript variants.[provided by RefSeq, Jun 2010 Expression: Ubiquitous expression in heart (RPKM 88.2), kidney (RPKM 80.7) and 25 other tissues See more
Preferred Names: ATP synthase subunit g, mitochondrial
Names: ATP synthase g chain, mitochondrial,
ATP synthase, H+ transporting, mitochondrial F0 complex, subunit G,
ATP synthase, H+ transporting, mitochondrial F1F0, subunit g,
ATP synthase, H+ transporting, mitochondrial Fo complex subunit G,
ATPase subunit G,
F1F0-type ATP synthase subunit g,
F1Fo-ATP synthase complex Fo membrane domain g subunit.
https://encrypted-tbn0.gstatic.com/images?q=tbn%3AANd9GcRKubCmmuGEstabx29_lFEqnxGOIZOLCII6thL7G4UIrNraNlh7&usqp=CAU
https://www.sciencedirect.com/science/article/pii/S0005272814000280
SIGMAR1(9p13.3)
https://www.ncbi.nlm.nih.gov/gene/10280
SIGMAR1provided by HGNC Official Full Name: sigma non-opioid intracellular receptor 1.Also known as SRBP; ALS16; DSMA2; OPRS1; SR-BP; SIG-1R; SR-BP1; sigma1R; hSigmaR1
Summary: This gene encodes a receptor protein that interacts with a variety of psychotomimetic drugs, including cocaine and amphetamines. The receptor is believed to play an important role in the cellular functions of various tissues associated with the endocrine, immune, and nervous systems. As indicated by its previous name, opioid receptor sigma 1 (OPRS1), the product of this gene was erroneously thought to function as an opioid receptor; it is now thought to be a non-opioid receptor. Mutations in this gene has been associated with juvenile amyotrophic lateral sclerosis 16. Alternative splicing of this gene results in transcript variants encoding distinct isoforms. [provided by RefSeq, Aug 2013 Expression Ubiquitous expression in liver (RPKM 44.6), duodenum (RPKM 22.5) and 25 other tissues See more
Preferred Names: sigma non-opioid intracellular receptor 1
Names: SR31747 binding protein 1,
aging-associated gene 8 protein,
sigma 1-type opioid receptor.
Names: SR31747 binding protein 1,
aging-associated gene 8 protein,
sigma 1-type opioid receptor.
FEATURES: NP_001269134.1 sigma non-opioid intracellular receptor 1 isoform 6
Conserved domains: https://www.ncbi.nlm.nih.gov/Structure/cdd/cddsrv.cgi?uid=282477
ERG2 and Sigma1 receptor like protein
This
family consists of the fungal C-8 sterol isomerase and mammalian sigma1
receptor. C-8 sterol isomerase (delta-8--delta-7 sterol isomerase),
catalyzes a reaction in ergosterol biosynthesis, which results in
unsaturation at C-7 in the B ring of sterols. Sigma 1 receptor is a low
molecular mass mammalian protein located in the endoplasmic reticulum,
which interacts with endogenous steroid hormones, such as progesterone
and testosterone. It also binds the sigma ligands, which are are a set
of chemically unrelated drugs including haloperidol, pentazocine, and
ditolylguanidine. Sigma1 effectors are not well understood, but sigma1
agonists have been observed to affect NMDA receptor function, the
alpha-adrenergic system and opioid analgesia.
- https://www.ncbi.nlm.nih.gov/pubmed/30832324/
- pharmacological Sig-1R activation a) enhances the autophagic flux in human cells, b) increases proteostasis capacity,the Sig-1R as an upstream modulator of canonical autophagy..
More than four decades passed since sigma receptors were first mentioned. Since then, existence of at least two receptor subtypes and their tissue distributions have been proposed. Nowadays, it is clear, that sigma receptors are unique ubiquitous proteins with pluripotent function, which can interact with so many different classes of proteins. As the endoplasmic resident proteins, they work as molecular chaperones - accompany various proteins during their folding, ensure trafficking of the maturated proteins between cellular organelles and regulate their functions. In the heart, sigma receptor type 1 is more dominant. Cardiac sigma 1 receptors regulate response to endoplasmic reticulum stress, modulates calcium signaling in cardiomyocyte and can affect function of voltage-gated ion channels. They contributed in pathophysiology of cardiac hypertrophy, heart failure and many other cardiovascular disorders. Therefore, sigma receptors are potential novel targets for specific treatment of cardiovascular diseases.
Muistiin 10.5. 2020.
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