E3 ubiquitin-protein ligase TRIM63, also known as "MuRF1" (Muscle Ring-Finger Protein-1), is an

enzyme Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as products ...

that in humans is encoded by the ''TRIM63''

gene In biology, the word gene (from , ; "... Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a b ...

. 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. 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 A ubiquitin ligase (also called an E3 ubiquitin ligase) is a protein that recruits an E2 ubiquitin-conjugating enzyme that has been loaded with ubiquitin, recognizes a protein substrate, and assists or directly catalyzes the transfer of ubiquiti ...

. Its major substrate is Myosin Heavy Chain (MHC, or

Myosin-2 Myosin-2 (myosin heavy chain 2) is a protein that in humans is encoded by the ''MYH2'' gene In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generatio ...

, or

MYH2 Myosin-2 (myosin heavy chain 2) is a protein that in humans is encoded by the ''MYH2'' gene In biology, the word gene (from , ; "... Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generatio ...

), meaning it induces the proteasome-mediated degradatin of MHC, by causing MHC to be ubiquitinated. MuRF1 is upregulated during skeletal muscle atrophy – and thus the degradation of myosin heavy chain, which is a major component of the

sarcomere A sarcomere (Greek σάρξ ''sarx'' "flesh", μέρος ''meros'' "part") 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 (called mus ...

, is an important mechanism in the breakdown of skeletal muscle under atrophy conditions 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 Advocates for Informed Choice, dba interACT or interACT Advocates for Intersex Youth, is a 501(c)(3) nonprofit organization using innovative strategies to advocate for the legal and human rights of children with intersex traits. The organizati ...

with

Titin Titin (contraction for Titan protein) (also called connectin) 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 th ...

, GMEB1 and

SUMO2 Small ubiquitin-related modifier 2 is a protein that in humans is encoded by the ''SUMO2'' gene. Function This gene encodes a protein that is a member of the SUMO (small ubiquitin-like modifier) protein family. It is a ubiquitin-like protein an ...

Regulation during skeletal muscle atrophy

During settings of skeletal muscle atrophy, the levels of Trim63/MuRF1 mRNA increase. , leading to breakdown of the

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

FOX proteins FOX (forkhead box) proteins are a family of transcription factors that play important roles in regulating the expression of genes involved in cell growth, proliferation, differentiation, and longevity. Many FOX proteins are important to embryonic ...

. Foxo1 or Foxo3 may regulate MuRF1. These factors are normally kept out of the nucleus by phosphorylation induced by a kinase called

Akt Protein kinase B (PKB), also known as Akt, is the collective name of a set of three serine/threonine-specific protein kinases that play key roles in multiple cellular processes such as glucose metabolism, apoptosis, cell proliferation, tran ...

. 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). 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.

Interactions

Regulation during skeletal muscle atrophy

Clinical significance

References

Further reading