(Suomennosta tiivistelmästä) Abstract
Sisältö: Murf-1:n (TRIM63) merkitys TITIINIKOMPLEKSILLE.
TITIINI muodostaa intrasarkomeerisen filamenttisysteemin selkärankaisten juovikkaassa lihaksessa ja sillä on elastisia ja sigaloivia ominaisuuksia ja se on sentraalinen mekaanisessa johtumisessa.TItiinissä on C-terminaalin lähellä ennen kianasidomaania konservoitunut Ig (IgA168)-ig(169) -ja FnIII(A170). moduli ja tämän ohella A168-A170), joka rekrytoi E3 ubikitiiniligaasin MURF-1 (TRIM63) filamenttiin. Arvellaan, että tämä interaktio säätelee filamentin vaihtuvuutta ja lihaksen troofista tilaa. Tutkijat selvittivät A168- A170 kiderakenteen ( matala kuoppamainen ja sen keskelä esiintyöntyvä silmukka) , luonnehtivat MURF-1 variantit ja tutkivat molempien komponenttien interaktioita eri menetelmin. MuRF-1:n C- terminaalinen helikaalinen domeeni on riittävä sitoutumaan tähän tutkittuun Titiini-jaksoon korkealla affiniteetilla, oletettavasti helikaali alue asettuu titiinijakson muodostamaan matalaan pintakuoppaan. Jaksosta esiintyöntyvä silmukka on avainvälittäjä MuRF-1-tunnistuksessa. Tutkijoitten löytö viittaa siihen, että tämä titiinijakso voisi toimia terapeuttisessa inhibitiossa MuRF-1-välitteiselle lihaksen vaihtuvuudelle: pienimolekyylinen sitoutuminen titiinin selviin struktuuuripiirteisiin voisi blokeerata MuRF-1 pääsyn titiiniin.
- Titin forms an intrasarcomeric filament system in vertebrate striated muscle, which has elastic and signaling properties and is thereby central to mechanotransduction. Near its C-terminus and directly preceding a kinase domain, titin contains a conserved pattern of Ig and FnIII modules (Ig(A168)-Ig(A169)-FnIII(A170), hereby A168-A170) that recruits the E3 ubiquitin-ligase MuRF-1 to the filament. This interaction is thought to regulate myofibril turnover and the trophic state of muscle. We have elucidated the crystal structure of A168-A170, characterized MuRF-1 variants by circular dichroism (CD) and SEC-MALS, and studied the interaction of both components by isothermal calorimetry, SPOTS blots, and pull-down assays. This has led to the identification of the molecular determinants of the binding. A168-A170 shows an extended, rigid architecture, which is characterized by a shallow surface groove that spans its full length and a distinct loop protrusion in its middle point. In MuRF-1, a C-terminal helical domain is sufficient to bind A168-A170 with high affinity. This helical region predictably docks into the surface groove of A168-A170. Furthermore, pull-down assays demonstrate that the loop protrusion in A168-A170 is a key mediator of MuRF-1 recognition. Our findings indicate that this region of titin could serve as a target to attempt therapeutic inhibition of MuRF-1-mediated muscle turnover, where binding of small molecules to its distinctive structural features could block MuRF-1 access.
Molecular Determinants for the... (PDF Download Available). Available from: https://www.researchgate.net/publication/6586953_Molecular_Determinants_for_the_recruitment_of_the_ubiquitin-ligase_MuRF-1_onton_M-line_titin [accessed Apr 08 2018].
8.4. 2018 HAKU: Titincomplex , TRIM
https://www.researchgate.net/publication/6586953_Molecular_Determinants_for_the_recruitment_of_the_ubiquitin-ligase_MuRF-1_onton_M-line_titin
Haku Telethonin degradation:
https://www.ncbi.nlm.nih.gov/pubmed/29271608
Muscle wasting is observed in the course of many diseases and also during physiological conditions (disuse, ageing). Skeletal muscle mass is largely controlled by the ubiquitin-proteasome system and thus by the ubiquitinating enzymes (E2s and E3s) that target substrates for subsequent degradation. MuRF1 is the only E3 ubiquitin ligase known to target contractile proteins (α-actin, myosins) during catabolic situations. However, MuRF1 depends on E2 ubiquitin-conjugating enzymes for ubiquitin chain formation on the substrates. MuRF1-E2 couples are therefore putative targets for preventing muscle wasting.
Five E2 enzymes physically interacted with MuRF1, namely, E2E1, E2G1, E2J1, E2J2, and E2L3. Moreover, we demonstrated that MuRF1-E2E1 and MuRF1-E2J1 interactions are facilitated by telethonin, a newly identified MuRF1 substrate. We next showed that the five identified E2s functionally interacted with MuRF1 since, in contrast to the non-interacting E2D2, their co-expression in HEK293T cells with MuRF1 led to increased telethonin degradation. Finally, we showed that telethonin governed the affinity between MuRF1 and E2E1 or E2J1.
https://www.researchgate.net/publication/6586953_Molecular_Determinants_for_the_recruitment_of_the_ubiquitin-ligase_MuRF-1_onton_M-line_titin
Haku Telethonin degradation:
https://www.ncbi.nlm.nih.gov/pubmed/29271608
Muscle wasting is observed in the course of many diseases and also during physiological conditions (disuse, ageing). Skeletal muscle mass is largely controlled by the ubiquitin-proteasome system and thus by the ubiquitinating enzymes (E2s and E3s) that target substrates for subsequent degradation. MuRF1 is the only E3 ubiquitin ligase known to target contractile proteins (α-actin, myosins) during catabolic situations. However, MuRF1 depends on E2 ubiquitin-conjugating enzymes for ubiquitin chain formation on the substrates. MuRF1-E2 couples are therefore putative targets for preventing muscle wasting.
Five E2 enzymes physically interacted with MuRF1, namely, E2E1, E2G1, E2J1, E2J2, and E2L3. Moreover, we demonstrated that MuRF1-E2E1 and MuRF1-E2J1 interactions are facilitated by telethonin, a newly identified MuRF1 substrate. We next showed that the five identified E2s functionally interacted with MuRF1 since, in contrast to the non-interacting E2D2, their co-expression in HEK293T cells with MuRF1 led to increased telethonin degradation. Finally, we showed that telethonin governed the affinity between MuRF1 and E2E1 or E2J1.
We report here the first MuRF1-E2s network, which may prove valuable for deciphering the precise mechanisms involved in the atrophying muscle programme and for proposing new therapeutical approaches.
©
2017 The Authors. Journal of Cachexia, Sarcopenia and Muscle published
by John Wiley & Sons Ltd on behalf of the Society on Sarcopenia,
Cachexia and Wasting Disorders.
20.3. 2018
https://www.ncbi.nlm.nih.gov/gene/84676#gene-expression
Tämä TRIM63 geeni tunnetaan myös muilla nimillä: IRF, SMRZ, MURF1, MURF2, RNF28.
Kyse on tyypillisestä RING Zn finger proteiinista, mutta sen sijoitatuma on erikoinen. Sitä on lähinnä sydänlihaksessa, juovikkaasa lihaksessa ja hieman myös löytyy ruokatorvesta. Sitä on myös silmän sädelihaksessa iiriksessä, siitä nimi IRF. Geenin koodamaa E3ubikitiiniligaasi sijoittuu sarkomeerissä Z- ja M-vyöhykkeiden myofibrilleihin. (Kts. tarkemmin: titiiniin, 2017).
Tällä proteiinilla on tärkeä osuus luurankolihaksen ja sydänlihaksen atrofiassa ja sitä tarvitaan myosiinin raskaan ja kevyen ketjun proteiinien sekä myosiinia sitovan proteiinin hajoitukseen ja lihastyyppinen kreatiinikinaasikin tarvitsee sitä.
MURF tarkoittaa: Muscle Ring Finger proteins. Ne modifioivat sydämen massaa ja funktiota ja toimivat säätelemällä ubikitiini-proteasomisysteemiä.MURF perheessä on 3 jäsentä. Alla on artikkeli joka selvittää niistä lisätietoja, kuten hypertrofista kardiomyopatiaa (HCM) sairastavien MURF-geeneistä.
TRIM63, Also known as IRF; SMRZ; MURF1; MURF2; RNF28
- Summary This gene encodes a member of the RING zinc finger protein family found in striated muscle and iris. The product of this gene is an E3 ubiquitin ligase that localizes to the Z-line and M-line lattices of myofibrils. This protein plays an important role in the atrophy of skeletal and cardiac muscle and is required for the degradation of myosin heavy chain proteins, myosin light chain, myosin binding protein, and for muscle-type creatine kinase. [provided by RefSeq, Feb 2012]
- Expression Biased expression in heart (RPKM 44.7) and esophagus (RPKM 2.8) See more
- Orthologs mouse all
Modifier genes
contribute to the diverse clinical manifestations of hypertrophic
cardiomyopathy (HCM), but are still largely unknown. Muscle ring finger
(MuRF) proteins are a class of muscle-specific ubiquitin E3-ligases that
appear to modulate cardiac mass and function by regulating the
ubiquitin-proteasome system. In this study we screened all the three
members of the MuRF family, MuRF1, MuRF2 and MuRF3, in 594 unrelated HCM
patients and 307 healthy controls by targeted resequencing. Identified
rare variants were confirmed by capillary Sanger sequencing
The prevalence of rare variants in both MuRF1 and MuRF2 in HCM patients was higher than that in control subjects (MuRF1 13/594 (2.2%) vs. 1/307 (0.3%), p = 0.04; MuRF2 22/594 (3.7%) vs. 2/307 (0.7%); p = 0.007). Patients with rare variants in MuRF1 or MuRF2 were younger (p = 0.04) and had greater maximum left ventricular wall thickness (p = 0.006) than those without such variants. Mutations in genes encoding sarcomere proteins were present in 19 (55.9%) of the 34 HCM patients with rare variants in MuRF1 and MuRF2. These data strongly supported that rare variants in MuRF1 and MuRF2 are associated with higher penetrance and more severe clinical manifestations of HCM. The findings suggest that dysregulation of the ubiquitin-proteasome system contributes to the pathogenesis of HCM.
Article2. Molecular
basis for the fold organization and sarcomeric targeting of the
muscle atrogin MuRF1. Franke B, et al. Open Biol, 2014
Mar 26. PMID 24671946, Free
PMC ArticleThe prevalence of rare variants in both MuRF1 and MuRF2 in HCM patients was higher than that in control subjects (MuRF1 13/594 (2.2%) vs. 1/307 (0.3%), p = 0.04; MuRF2 22/594 (3.7%) vs. 2/307 (0.7%); p = 0.007). Patients with rare variants in MuRF1 or MuRF2 were younger (p = 0.04) and had greater maximum left ventricular wall thickness (p = 0.006) than those without such variants. Mutations in genes encoding sarcomere proteins were present in 19 (55.9%) of the 34 HCM patients with rare variants in MuRF1 and MuRF2. These data strongly supported that rare variants in MuRF1 and MuRF2 are associated with higher penetrance and more severe clinical manifestations of HCM. The findings suggest that dysregulation of the ubiquitin-proteasome system contributes to the pathogenesis of HCM.
- Human molecular genetic and functional studies identify TRIM63, encoding Muscle RING Finger Protein 1, as a novel gene for human hypertrophic cardiomyopathy. Chen SN, et al. Circ Res, 2012 Sep 14. PMID 22821932, Free PMC Article A delicate balance between protein synthesis and degradation maintains cardiac size and function. TRIM63 encoding Muscle RING Finger 1 (MuRF1) maintains muscle protein homeostasis by tagging the sarcomere proteins with ubiquitin for subsequent degradation by the ubiquitin-proteasome system (UPS). TRIM63 mutations, identified in patients with HCM, impart loss-of-function effects on E3 ligase activity and are probably causal mutations in HCM. The findings implicate impaired protein degradation in the pathogenesis of HCM.
- Anabolic effects of exercise training in patients with advanced chronic heart failure (NYHA IIIb): impact on ubiquitin-protein ligases expression and skeletal muscle size. Höllriegel R, et al. Int J Cardiol, 2013 Aug 10. PMID 22445192 Patients with advanced chronic heart failure (CHF) are characterized by progressive muscle wasting. The two E3-ligases Rnf28 and Atrogin-1 controlling the activationof the ubiquitinproteasome system might be of importance for the regulation of muscle size. Given the convincing effect of regular physical exercise training (ET) in CHF, it was the aim of the present trialelucidate, whether ET affects both mentioned enzymes in CHF and whether this is associated with an increase in skeletal muscle mass.CONCLUSION: In patients with advanced CHF, regular physical exercise training led to a decrease in Rnf28 expression in the skeletal muscle. This was linked to an increase in skeletal muscle cross sectional area, supporting the notion that ET has anti-catabolic properties in CHF.
- Targeting the ubiquitin E3 ligase MuRF1 to inhibit muscle atrophy. Eddins MJ, et al. Cell Biochem Biophys, 2011 Jun. PMID 21448668 Progressive muscle wasting, also known as myopathy or muscle atrophy is a debilitating and life-threatening disorder. Myopathy is a pathological condition of many diseases including cancer, diabetes, COPD, and AIDS and is a natural consequence of inactivity and aging (sarcopenia). Muscle atrophy occurs when there is a net loss of muscle mass resulting in a change in the balance between protein synthesis and protein degradation. The ubiquitin pathway and specific ubiquitin pathway enzymes have been directly implicated in the progression of atrophy. The ubiquitin E3 ligase Muscle-specific RING Finger E3 ligase (MuRF1) is upregulated and increases protein degradation and muscle wasting in numerous muscle atrophy models. The inhibition of MuRF1 could be a novel mechanism to prevent or reverse muscle wasting associated with various pathologies. We screened a small molecule library for inhibitors to MuRF1 activity and identified P013222, an inhibitor of MuRF1 autoubiquitylation. Further, P013222 was shown to inhibit MuRF1-dependent substrate ubiquitylation, and was active in inhibiting MuRF1 in a cellular atrophy model. Thus MuRF1 can be targeted in a specific manner and produce positive results in cellular atrophy models.
GeneRIFs: Gene References Into FunctionsWhat's a GeneRIF?
-
Clinical trials involving in patients with osteoporosis have reported that activated vitamin D3 (1α,25(OH)2D3, calcitriol) can prevent falling by acting on the skeletal muscles. However, pharmacological mechanisms of 1α,25(OH)2D3 with respect to skeletal muscle hypertrophy or atrophy are still poorly understood. Therefore, we examined changes in the expression of several related genes in human myotubes to test whether 1α,25(OH)2D3 influences hypertrophy and atrophy of skeletal muscle. Myotubes treated with 1α,25(OH)2D3 increased interleukin-6 (IL-6) expression and inhibited expression of tumor necrosis factor alpha (TNF-α), whereas the expression of insulin-like growth factor-1 (IGF-1) that is involved in muscle hypertrophy was not affected. However, 1α,25(OH)2D3 treatment significantly inhibited the expression of muscle atrophy F-box (MAFbx) and muscle RING finger 1 (MuRF1), ubiquitin ligases involved in muscle atrophy. The analysis of pathways using microarray data suggested that 1α,25(OH)2D3 upregulates AKT-1 by inhibiting the expression of protein phosphatase 2 (PP2A), a phosphatase acting on AKT-1, in the phosphatidylinositol 3-kinase (PI3K)/AKT signaling pathway, thereby inhibiting the expression of ubiquitin ligases. Thus, this study showed that 1α,25(OH)2D3 might have an inhibitory effect on the expression of MAFbx and MuRF1 in skeletal muscle and a suppressive effect on muscle degradation in patients with osteoporosis.
-
Seletal
muscle atrophy induced by Angiotensin II involves activation of
MuRF1 expression.
Muistiin 20.3. 2018. Huom. asianmukaisella treenauksella on etua sydänlihaksen kuntoon, D-vitamiinikin eduksi
Kromosomi 1:n TRIM-proteiineja
TRIM63 peptidisekvenssiä:
Kromosomi 1:n TRIM-proteiineja
TRIM63 peptidisekvenssiä:
/translation=
"MDYKSSLIQDGNPMENLEKQLICPICLEMFTKPVVILPCQHNLC
RKCANDIFQAANPYWTSRGSSVSMSGGRFRCPTCRHEVIMDRHGVYGLQRNLLVENII
DIYKQECSSRPLQKGSHPMCKEHEDEKINIYCLTCEVPTCSMCKVFGIHKACEVAPLQ
SVFQGQKTELNNCISMLVAGNDRVQTIITQLEDSRRVTKENSHQVKEELSQKFDTLYA
ILDEKKSELLQRITQEQEKKLSFIEALIQQYQEQLDKSTKLVETAIQSLDEPGGATFL
LTAKQLIKSIVEASKGCQLGKTEQGFENMDFFTLDLEHIADALRAIDFGTDEEEEEFI
EEEDQEEEESTEGKEEGKKFIYLHSFVPSFIPQQSEVPTVCEALC"
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