TRIM63

TRIM63
Available structures
PDB	Ortholog search: PDBe RCSB
List of PDB id codes
	3DDT, 4M3L, 2D8U
Identifiers
Aliases	TRIM63 , IRF, MURF1, MURF2, RNF28, SMRZ, tripartite motif containing 63
External IDs	OMIM: 606131 MGI: 2447992 HomoloGene: 41878 GeneCards: TRIM63
Gene location (Human)
Chr.	Chromosome 1 (human)
End	26,068,436 bp
Gene location (Mouse)
Chr.	Chromosome 4 (mouse)
End	134,056,940 bp
RNA expression pattern
	Top expressed in
	gastrocnemius muscle; ; tibialis anterior muscle; ; quadriceps femoris muscle; ; vastus lateralis muscle; ; deltoid muscle; ; biceps brachii; ; right ventricle; ; body of tongue; ; vena cava; ; superior surface of tongue;
	Top expressed in
	knee joint; ; tibialis anterior muscle; ; triceps brachii muscle; ; soleus muscle; ; vastus lateralis muscle; ; temporal muscle; ; sternocleidomastoid muscle; ; digastric muscle; ; intercostal muscle; ; skeletal muscle tissue;
	More reference expression data
	More reference expression data
Gene ontology
Molecular function	zinc ion binding ; protein binding ; titin binding ; signal transducer activity ; metal ion binding ; ubiquitin-protein transferase activity ; transferase activity ;
Cellular component	cytoplasm ; M band ; contractile fiber ; Z disc ; microtubule ; nucleus ; intracellular anatomical structure ;
Biological process	skeletal muscle atrophy ; muscle contraction ; response to glucocorticoid ; response to interleukin-1 ; protein ubiquitination ; response to electrical stimulus involved in regulation of muscle adaptation ; signal transduction ; negative regulation of cardiac muscle hypertrophy ;
	Sources:Amigo / QuickGO
Orthologs
	84676
	433766
	ENSG00000158022
	ENSMUSG00000028834
	Q969Q1
	Q38HM4
	NM_032588
	NM_001039048 ; NM_001369245
	NP_115977
	n/a
	Wikidata
View/Edit Human	View/Edit Mouse

Last updated January 06, 2024

E3 ubiquitin-protein ligase TRIM63, also known as "MuRF1" (Muscle Ring-Finger Protein-1),^[5] is an enzyme that in humans is encoded by the TRIM63 gene.^[6]^[7]^[8]

This gene encodes a member of the RING zinc finger protein family found in striated muscle and iris. The product of this gene is localized to the Z-line and M-line lattices of myofibrils, where titin's N-terminal and C-terminal regions respectively bind to the sarcomere. In vitro binding studies have shown that this protein also binds directly to titin near the region of titin containing kinase activity. Another member of this protein family binds to microtubules. Since these family members can form heterodimers, this suggests that these proteins may serve as a link between titin kinase and microtubule-dependent signal pathways in muscle.^[8]

The protein encoded by the Trim63 gene is also called MuRF1. MuRF1 is the name most commonly used in the literature, and it stands for "Muscle RING Finger 1." Structurally, there are two closely related MuRFs, MuRF2 and MuRF3. These also have TRIM codes: MuRF2 is TRIM55; MuRF3 is TRIM54.

Interactions

Trim63/MuRF1 has been shown to be an E3 ubiquitin ligase. Its major substrate is Myosin Heavy Chain (MHC, or Myosin-2, or MYH2), meaning it induces the proteasome-mediated degradatin of MHC, by causing MHC to be ubiquitinated.^[9] MuRF1 is upregulated during skeletal muscle atrophy – and thus the degradation of myosin heavy chain, which is a major component of the sarcomere, is an important mechanism in the breakdown of skeletal muscle under atrophy conditions ^[5] MuRF1 has been shown to be upregulated during denervation, administration of glucocorticoids, immobilization, and casting (when a cast is applied to a limb, in order to immobilize it). All of these settings cause skeletal muscle atrophy.

TRIM63/MuRF1 has been shown to interact with Titin,^[6] GMEB1 ^[10] and SUMO2.^[7]

Regulation during skeletal muscle atrophy

During settings of skeletal muscle atrophy, the levels of Trim63/MuRF1 mRNA increase.,^[5] leading to breakdown of the sarcomere.

This was found to be due to regulation of gene expression of Trim63/MuRF1 by the FOXO (or Forkhead) family of transcription factors.;^[11] see also FOX proteins.

Foxo1 or Foxo3 may regulate MuRF1. These factors are normally kept out of the nucleus by phosphorylation induced by a kinase called Akt. When Akt is inactivated, or less active, Foxo1 or Foxo3 can then transport to the nucleus, and induce expression of MuRF1.

Clinical significance

Recently, it has been suggested that TRIM63/MuRF1 is associated with an autosomal-recessive form of hypertrophic cardiomyopathy (HCM).^[12] In this paper, the authors describe that individuals harboring homozygous or compound heterozygous rare variants in TRIM63/MuRF1 show a peculiar HCM phenotype, characterized by concentric left ventricular (LV) hypertrophy (50% of patients) and a high rate of LV dysfunction (20%). This finding suggests that Myosin Heavy Chain levels may be dysregulated in the heart in the absence of MuRF1, leading to pathology.

Upregulation of MuRF1/Trim63 mRNA is regularly used as an indicator that active skeletal muscle atrophy is occurring.

Related Research Articles

A myofibril is a basic rod-like organelle of a muscle cell. Skeletal muscles are composed of long, tubular cells known as muscle fibers, and these cells contain many chains of myofibrils. Each myofibril has a diameter of 1–2 micrometres. They are created during embryonic development in a process known as myogenesis.

<span class="mw-page-title-main">Sarcomere</span> Repeating unit of a myofibril in a muscle cell

A sarcomere is the smallest functional unit of striated muscle tissue. It is the repeating unit between two Z-lines. Skeletal muscles are composed of tubular muscle cells which are formed during embryonic myogenesis. Muscle fibers contain numerous tubular myofibrils. Myofibrils are composed of repeating sections of sarcomeres, which appear under the microscope as alternating dark and light bands. Sarcomeres are composed of long, fibrous proteins as filaments that slide past each other when a muscle contracts or relaxes. The costamere is a different component that connects the sarcomere to the sarcolemma.

<span class="mw-page-title-main">Titin</span> Largest-known protein in human muscles

Titin is a protein that in humans is encoded by the TTN gene. Titin is a giant protein, greater than 1 µm in length, that functions as a molecular spring that is responsible for the passive elasticity of muscle. It comprises 244 individually folded protein domains connected by unstructured peptide sequences. These domains unfold when the protein is stretched and refold when the tension is removed.

<span class="mw-page-title-main">Myofilament</span> The two protein filaments of myofibrils in muscle cells

Myofilaments are the three protein filaments of myofibrils in muscle cells. The main proteins involved are myosin, actin, and titin. Myosin and actin are the contractile proteins and titin is an elastic protein. The myofilaments act together in muscle contraction, and in order of size are a thick one of mostly myosin, a thin one of mostly actin, and a very thin one of mostly titin.

<span class="mw-page-title-main">Nebulin</span> Protein-coding gene in the species Homo sapiens

Nebulin is an actin-binding protein which is localized to the thin filament of the sarcomeres in skeletal muscle. Nebulin in humans is coded for by the gene NEB. It is a very large protein and binds as many as 200 actin monomers. Because its length is proportional to thin filament length, it is believed that nebulin acts as a thin filament "ruler" and regulates thin filament length during sarcomere assembly and acts as the coats the actin filament. Other functions of nebulin, such as a role in cell signaling, remain uncertain.

<span class="mw-page-title-main">Myomesin</span>

Myomesin is a protein family found in the M-line of the sarcomere structure. Myomesin has various forms throughout the body in striated muscles with specialized functions. This includes both slow and fast muscle fibers. Myomesin are made of 13 domains including a unique N-terminal followed by two immunoglobulin-like (Ig) domains, five fibronectin type III (Fn) domains, five more Ig domains. These domains all promote binding which indicates that myomesin is regulated through binding.

Calpain-3 is a protein that in humans is encoded by the CAPN3 gene.

Alpha-actinin-2 is a protein which in humans is encoded by the ACTN2 gene. This gene encodes an alpha-actinin isoform that is expressed in both skeletal and cardiac muscles and functions to anchor myofibrillar actin thin filaments and titin to Z-discs.

The myosin-binding protein C, cardiac-type is a protein that in humans is encoded by the MYBPC3 gene. This isoform is expressed exclusively in heart muscle during human and mouse development, and is distinct from those expressed in slow skeletal muscle (MYBPC1) and fast skeletal muscle (MYBPC2).

Telethonin, also known as Tcap, is a protein that in humans is encoded by the TCAP gene. Telethonin is expressed in cardiac and skeletal muscle at Z-discs and functions to regulate sarcomere assembly, T-tubule function and apoptosis. Telethonin has been implicated in several diseases, including limb-girdle muscular dystrophy, hypertrophic cardiomyopathy, dilated cardiomyopathy and idiopathic cardiomyopathy.

Myotilin is a protein that in humans is encoded by the MYOT gene. Myotilin also known as TTID is a muscle protein that is found within the Z-disc of sarcomeres.

Obscurin is a protein that in humans is encoded by the OBSCN gene. Obscurin belongs to the family of giant sarcomeric signaling proteins that includes titin and nebulin. Obscurin is expressed in cardiac and skeletal muscle, and plays a role in the organization of myofibrils during sarcomere assembly. A mutation in the OBSCN gene has been associated with hypertrophic cardiomyopathy and altered obscurin protein properties have been associated with other muscle diseases.

Ankyrin Repeat, PEST sequence and Proline-rich region (ARPP), also known as Ankyrin repeat domain-containing protein 2 is a protein that in humans is encoded by the ANKRD2 gene. ARPP is a member of the muscle ankyrin repeat proteins (MARP), which also includes CARP and DARP, and is highly expressed in cardiac and skeletal muscle and in other tissues. Expression of ARPP has been shown to be altered in patients with dilated cardiomyopathy and amyotrophic lateral sclerosis. A role for Ankrd2 in tumor progression and metastases spreading has also been described.

Ankyrin repeat domain-containing protein 1, or Cardiac ankyrin repeat protein is a protein that in humans is encoded by the ANKRD1 gene also known as CARP. CARP is highly expressed in cardiac and skeletal muscle, and is a transcription factor involved in development and under conditions of stress. CARP has been implicated in several diseases, including dilated cardiomyopathy, hypertrophic cardiomyopathy, and several skeletal muscle myopathies.

Tripartite motif-containing protein 32 is a protein that in humans is encoded by the TRIM32 gene. Since its discovery in 1995, TRIM32 has been shown to be implicated in a number of diverse biological pathways.

Myopalladin is a protein that in humans is encoded by the MYPN gene. Myopalladin is a muscle protein responsible for tethering proteins at the Z-disc and for communicating between the sarcomere and the nucleus in cardiac and skeletal muscle

<span class="mw-page-title-main">MYOM1</span> Protein-coding gene in humans

Myomesin-1 is a protein that in humans is encoded by the MYOM1 gene. Myomesin-1 is expressed in muscle cells and functions to stabilize the three-dimensional conformation of the thick filament. Embryonic forms of Myomesin-1 have been detected in dilated cardiomyopathy.

Tripartite motif-containing protein 55 is a protein that in humans is encoded by the TRIM55 gene.

F-box only protein 32, also known as "MAFbx", for "Muscle Atrophy F-box gene", and "Atrogin-1," is a protein that in humans is encoded by the FBXO32 gene.

Myomesin-2, also known as M-protein is a protein that in humans is encoded by the MYOM2 gene. M-protein is expressed in adult cardiac muscle and fast skeletal muscle, and functions to stabilize the three-dimensional arrangement of proteins comprising M-band structures in a sarcomere.

References

1 2 3 GRCh38: Ensembl release 89: ENSG00000158022 - Ensembl, May 2017
1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000028834 - Ensembl, May 2017
↑ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
↑ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
1 2 3 Bodine SC, Latres E, Baumhueter S, Lai VK, Nunez L, Clarke BA, Poueymirou WT, Panaro FJ, Na E, Dharmarajan K, Pan ZQ, Valenzuela DM, DeChiara TM, Stitt TN, Yancopoulos GD, Glass DJ (November 2001). "Identification of ubiquitin ligases required for skeletal muscle atrophy". Science. 294 (5547): 1704–1708. Bibcode:2001Sci...294.1704B. doi: 10.1126/science.1065874 . PMID 11679633. S2CID 37349291.
1 2 Centner T, Yano J, Kimura E, McElhinny AS, Pelin K, Witt CC, Bang ML, Trombitas K, Granzier H, Gregorio CC, Sorimachi H, Labeit S (March 2001). "Identification of muscle specific ring finger proteins as potential regulators of the titin kinase domain". Journal of Molecular Biology. 306 (4): 717–726. doi:10.1006/jmbi.2001.4448. PMID 11243782.
1 2 Dai KS, Liew CC (June 2001). "A novel human striated muscle RING zinc finger protein, SMRZ, interacts with SMT3b via its RING domain". The Journal of Biological Chemistry. 276 (26): 23992–23999. doi: 10.1074/jbc.M011208200 . PMID 11283016.
1 2 "Entrez Gene: TRIM63 tripartite motif-containing 63".
↑ Clarke BA, Drujan D, Willis MS, Murphy LO, Corpina RA, Burova E, Rakhilin SV, Stitt TN, Patterson C, Latres E, Glass DJ (November 2007). "The E3 Ligase MuRF1 degrades myosin heavy chain protein in dexamethasone-treated skeletal muscle". Cell Metabolism. 6 (5): 376–385. doi: 10.1016/j.cmet.2007.09.009 . PMID 17983583.
↑ McElhinny AS, Kakinuma K, Sorimachi H, Labeit S, Gregorio CC (April 2002). "Muscle-specific RING finger-1 interacts with titin to regulate sarcomeric M-line and thick filament structure and may have nuclear functions via its interaction with glucocorticoid modulatory element binding protein-1". The Journal of Cell Biology. 157 (1): 125–136. doi:10.1083/jcb.200108089. PMC 2173255 . PMID 11927605.
↑ Stitt TN, Drujan D, Clarke BA, Panaro F, Timofeyva Y, Kline WO, Gonzalez M, Yancopoulos GD, Glass DJ (May 2004). "The IGF-1/PI3K/Akt pathway prevents expression of muscle atrophy-induced ubiquitin ligases by inhibiting FOXO transcription factors". Molecular Cell. 14 (3): 395–403. doi: 10.1016/s1097-2765(04)00211-4 . PMID 15125842.
↑ Salazar-Mendiguchía J, Ochoa JP, Palomino-Doza J, Domínguez F, Díez-López C, Akhtar M, Ramiro-León S, Clemente MM, Pérez-Cejas A, Robledo M, Gómez-Díaz I, Peña-Peña ML, Climent V, Salmerón-Martínez F, Hernández C, García-Granja PE, Mogollón MV, Cárdenas-Reyes I, Cicerchia M, García-Giustiniani D, Lamounier A, Gil-Fournier B, Díaz-Flores F, Salguero R, Santomé L, Syrris P, Olivé M, García-Pavía P, Ortiz-Genga M, Elliott PM, Monserrat L (September 2020). "Mutations in TRIM63 cause an autosomal-recessive form of hypertrophic cardiomyopathy". Heart. 106 (17): 1342–1348. doi:10.1136/heartjnl-2020-316913. PMC 7476281 . PMID 32451364.