Myotilin is a

protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, res ...

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

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 ...

. Myotilin (myofibrillar titin-like protein) also known as TTID (TiTin Immunoglobulin Domain) is a muscle protein that is found within the

Z-disc 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 musc ...

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 ...

Structure

Myotilin is a 55.3 kDa protein composed of 496 amino acids. Myotilin was originally identified as a novel alpha-actinin binding partner with two Ig-like domains, that localized to the

. The I-type Ig-like domains reside at the C-terminal half, and are most homologous to Ig domains 2-3 of

palladin 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. Discovery Palladin was characterised independently by two re ...

and Ig domains 4-5 of myopalladin and more distantly related to

Ig domains 7 and 8 of

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 ...

. The C-terminal region hosts the binding sites for Z-band proteins, and 2 Ig domains are the site of homodimerization for myotilin. 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. 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 Actin is a family of globular multi-functional proteins that form microfilaments in the cytoskeleton, and the thin filaments in muscle fibrils. It is found in essentially all eukaryotic cells, where it may be present at a concentration of ov ...

, Filamin C, FATZ-1, FATZ-2 and ZASP.

Function

Myotilin is a structural protein that, along with

and alpha-actinin give structural integrity to

s at

s in striated muscle. Myotilin induces the formation of actin bundles in vitro and in non-muscle cells. A ternary complex myotilin/

/ alpha-actinin can be observed in vitro and

bundles formed under these conditions appear more tightly packed than those induced by alpha-actinin alone. It was demonstrated that myotilin stabilizes

F-actin Actin is a family of globular multi-functional proteins that form microfilaments in the cytoskeleton, and the thin filaments in muscle fibrils. It is found in essentially all eukaryotic cells, where it may be present at a concentration of ov ...

by slowing down the disassembly rate. Ectopic overexpression of truncated myotilin causes the disruption of nascent myofibrils and the co-accumulation of myotilin and

in amorphous cytoplasmic precipitates. In mature

s, wild-type myotilin colocalizes with alpha-actinin and

, showing the striated pattern typical of sarcomeric proteins. Targeted disruption of the myotilin gene in mice does not cause significant alterations in muscle function. On the other hand, transgenic mice with mutated myotilin develop muscle dystrophy.

Clinical significance

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. The mechanism underlying the pathology is still under investigation. It has been shown that actin binding properties of myotilin housing pathogenic mutations (

Ser Ser or SER may refer to: Places * Ser, a village in Bogdand Commune, Satu Mare County, Romania * Serpens (Ser), an astronomical constellation of the northern hemisphere * Serres, known as Ser in Serbian, a city in Macedonia, Greece Organization ...

55 Phe, Thr57

Ile Ile may refer to: * iLe, a Puerto Rican singer * Ile District (disambiguation), multiple places * Ilé-Ifẹ̀, an ancient Yoruba city in south-western Nigeria * Interlingue (ISO 639:ile), a planned language * Isoleucine, an amino acid * Anothe ...

60 Cys, and

) are normal, albeit with a slower rate of degradation. Surprisingly, YFP-fusion constructs of myotilin mutants (

55 Phe,

, Thr57

60 Cys,

60 Phe,

, Arg405 Lys) localized normally to Z-discs and exhibited normal dynamics in muscle cells.

References

External links

*
GeneReviews/NIH/NCBI/UW entry on Myofibrillar Myopathy
* {{Muscle tissue Human proteins

Structure

Function

Clinical significance

References

Further reading

External links