| MYOT | |||||||||||||||||||||||||||||||||||||||||||||||||||
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| Aliases | MYOT , LGMD1, LGMD1A, MFM3, TTID, TTOD, myotilin | ||||||||||||||||||||||||||||||||||||||||||||||||||
| External IDs | OMIM: 604103 MGI: 1889800 HomoloGene: 4942 GeneCards: MYOT | ||||||||||||||||||||||||||||||||||||||||||||||||||
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| Wikidata | |||||||||||||||||||||||||||||||||||||||||||||||||||
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Myotilin is a protein that in humans is encoded by the MYOT gene. [5] [6] [7] Myotilin (myofibrillar titin-like protein) also known as TTID (TiTin Immunoglobulin Domain) is a muscle protein that is found within the Z-disc of sarcomeres.
Myotilin is a 55.3 kDa protein composed of 496 amino acids. [8] Myotilin was originally identified as a novel alpha-actinin binding partner with two Ig-like domains, that localized to the Z-disc. [9] The I-type Ig-like domains reside at the C-terminal half, and are most homologous to Ig domains 2-3 of palladin and Ig domains 4-5 of myopalladin and more distantly related to Z-disc Ig domains 7 and 8 of titin. The C-terminal region hosts the binding sites for Z-band proteins, and 2 Ig domains are the site of homodimerization for myotilin. [10] By contrast, the N-terminal part of myotilin is unique, consisting of a serine-rich region with no homology to known proteins. Several disease-associated mutations involve serine residues within the serine-rich domain. [11] Myotilin expression in human tissues is mainly restricted to striated muscles and nerves. In muscles, myotilin is predominantly found within the Z-discs. Myotilin forms homodimers and binds alpha-actinin, actin, [12] Filamin C, [13] FATZ-1, [14] FATZ-2 [14] and ZASP. [15]
Myotilin is a structural protein that, along with titin and alpha-actinin give structural integrity to sarcomeres at Z-discs in striated muscle. Myotilin induces the formation of actin bundles in vitro and in non-muscle cells. A ternary complex myotilin/actin/alpha-actinin can be observed in vitro and actin bundles formed under these conditions appear more tightly packed than those induced by alpha-actinin alone. It was demonstrated that myotilin stabilizes F-actin by slowing down the disassembly rate. Ectopic overexpression of truncated myotilin causes the disruption of nascent myofibrils and the co-accumulation of myotilin and titin in amorphous cytoplasmic precipitates. In mature sarcomeres, wild-type myotilin colocalizes with alpha-actinin and Z-disc titin, showing the striated pattern typical of sarcomeric proteins. Targeted disruption of the myotilin gene in mice does not cause significant alterations in muscle function. [16] On the other hand, transgenic mice with mutated myotilin develop muscle dystrophy. [17]
Myotilin is mutated in various forms of muscular dystrophy: Limb-Girdle Muscular Dystrophy type 1A (LGMD1A), Myofibrillar Myopathy (MFM), Spheroid Body Myopathy and Distal Myopath. [11] The mechanism underlying the pathology is still under investigation. It has been shown that actin binding properties of myotilin housing pathogenic mutations (Ser55Phe, Thr57Ile, Ser60Cys, and Ser95Ile) are normal, [18] albeit with a slower rate of degradation. [19] Surprisingly, YFP-fusion constructs of myotilin mutants (Ser55Phe, Ser55Ile, Thr57Ile, Ser60Cys, Ser60Phe, Ser95Ile, Arg405Lys) localized normally to Z-discs and exhibited normal dynamics in muscle cells. [20]
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.
Plectin is a giant protein found in nearly all mammalian cells which acts as a link between the three main components of the cytoskeleton: actin microfilaments, microtubules and intermediate filaments. In addition, plectin links the cytoskeleton to junctions found in the plasma membrane that structurally connect different cells. By holding these different networks together, plectin plays an important role in maintaining the mechanical integrity and viscoelastic properties of tissues.
Dysferlin also known as dystrophy-associated fer-1-like protein is a protein that in humans is encoded by the DYSF gene. Dysferlin is linked with plasma membrane repair., stabilization of calcium signaling and the development of the T-tubule system of the muscle A defect in the DYSF gene, located on chromosome 2p12-14, results in several types of muscular dystrophy; including Miyoshi myopathy (MM), Limb-girdle muscular dystrophy type 2B (LGMD2B) and Distal Myopathy (DM). A reduction or absence of dysferlin, termed dysferlinopathy, usually becomes apparent in the third or fourth decade of life and is characterised by weakness and wasting of various voluntary skeletal muscles. Pathogenic mutations leading to dysferlinopathy can occur throughout the DYSF gene.
Zaspopathy, also called ZASP-related myofibril myopathy, is a novel autosomal dominant form of progressive muscular dystrophy, first described in 2005.
Palladin is a protein that in humans is encoded by the PALLD gene. Palladin is a component of actin-containing microfilaments that control cell shape, adhesion, and contraction.
Calpain-3 is a protein that in humans is encoded by the CAPN3 gene.
Actin, cytoplasmic 2, or gamma-actin is a protein that in humans is encoded by the ACTG1 gene. Gamma-actin is widely expressed in cellular cytoskeletons of many tissues; in adult striated muscle cells, gamma-actin is localized to Z-discs and costamere structures, which are responsible for force transduction and transmission in muscle cells. Mutations in ACTG1 have been associated with nonsyndromic hearing loss and Baraitser-Winter syndrome, as well as susceptibility of adolescent patients to vincristine toxicity.
Alpha-actinin-3, also known as alpha-actinin skeletal muscle isoform 3 or F-actin cross-linking protein, is a protein that in humans is encoded by the ACTN3 gene located on chromosome 11. All people have two copies (alleles) of this 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.
Filamin-C (FLN-C) also known as actin-binding-like protein (ABPL) or filamin-2 (FLN2) is a protein that in humans is encoded by the FLNC gene. Filamin-C is mainly expressed in cardiac and skeletal muscles, and functions at Z-discs and in subsarcolemmal regions.
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.
Delta-sarcoglycan is a protein that in humans is encoded by the SGCD gene.
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 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.
Cysteine and glycine-rich protein 3 also known as cardiac LIM protein (CLP) or muscle LIM protein (MLP) is a protein that in humans is encoded by the CSRP3 gene.
LIM domain binding 3 (LDB3), also known as Z-band alternatively spliced PDZ-motif (ZASP), is a protein which in humans is encoded by the LDB3 gene. ZASP belongs to the Enigma subfamily of proteins and stabilizes the sarcomere during contraction, through interactions with actin in cardiac and skeletal muscles. Mutations in the ZASP gene has been associated with several muscular diseases.
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
Myozenin-1 is a protein that in humans is encoded by the MYOZ1 gene.
Chaperone-assisted selective autophagy is a cellular process for the selective, ubiquitin-dependent degradation of chaperone-bound proteins in lysosomes.
