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Syncoilin

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syncoilin
Identifiers
SymbolSYNC1
NCBI gene81493
HGNC28897
OMIM611750
RefSeqNM_030786
UniProtQ9H7C4
Other data
LocusChr. 1 p35.1-p33
Search for
StructuresSwiss-model
DomainsInterPro

Discovery

Syncoilin is a muscle-specific atypical type III intermediate filament protein encoded in the human by the gene SYNC.[1] It was first isolated as a binding partner to α-dystrobrevin, as determined by a yeast two-hybrid assay.[2]

Later, a yeast two-hybrid method was used to demonstrate that syncoilin is a binding partner of desmin.[3] These binding partners suggest that syncoilin acts as a mechanical "linker" between the sarcomere Z-disk (where desmin is localized) and the dystrophin-associated protein complex (where α-dystrobrevin is localized). However, the specific in vivo functions of syncoilin have not yet been determined.

Through the use of Western blotting techniques, a second species of syncoilin was found. This species was 55kDa in size, whereas the original species of syncoilin was 64kDa in size. This discovery inspired scientists to use gene splicing to identify two new isoforms called SYNC2 and SYNC3.[4]

Abnormally high levels of syncoilin have been shown to be a characteristic of neuromuscular wasting diseases such as desminopathy[5] and muscular dystrophy.[6] Therefore, syncoilin is being explored as a promising marker of neuromuscular disease.

Structure

Syncoilin is characterized as an intermediate filament and contains the key structural features that make up intermediate filaments such as a head region, linker regions, alpha helices, and a tail region. Each protein that is classified as an intermediate filament will vary in the size and shape of their head and tail regions.[7]

More specifically, syncoilin is structurally defined by its central rod domain that forms a coil made up of 4 subunits, an α-helical region separated by flexible linkers, a N-terminal head domain, and a C-terminal tail domain.[7] The isoform of syncoilin, SYNC 3, has a much different structure than the original protein filament. This isoform has a truncated rod domain and lacks a C-terminal tail region.[4]

Because the tail of syncoilin is so short, it is hypothesized that this affects the ability of syncoilin to form other filaments.[7] Syncoilin is different from other type III intermediate filaments because it has a unique N-terminal that is unlike any other protein.[8] Syncoilin does not have the capability of forming dimers spontaneously like other filaments.[9]

Function

The most important job of syncoilin is to provide linkage between DAPC proteins and α-dystrobrevin. Studies have yet to determine if the binding of synacoilin to DAPC proteins and α-dystrobrevin occurs simultaneously.[9] Syncoilin, like other intermediate filaments, is also necessary for the supporting the structure of the muscle fiber.[10]

However, syncoilin does not serve the same function as most other intermediate filaments. It can be used in an attempt to fix muscle that has been damaged through up-regulation.[5] Studies have shown that the upregulation of syncoilin is not just harmful to muscle fibers. Upregulation has also been proven to help with muscle membrane stability.[5]

Hepatic stellate cells are a specialized tissue type in the body that require syncoilin intermediate filaments. When an injury occurs to the liver, expression of intermediate filaments such as syncoilin and an increase in α-smooth muscle cells (α-SMA). It is now used to help mark activated hepatic stellate cells after being identified in an experiment done on primary liver cells in mice. In this study, syncoilin isoforms SYNC1 and SYNC2 were highly expressed during in vivo activation of hepatic stellate cells.[10]

Location

Syncoilin is found in skeletal and cardiac muscle which is similar to its binding protein desmin.[9] The region of skeletal muscle that houses most of the syncoilin is the sarcolemma.[7] If the muscle tissue is dissected further into individual muscle fibers, it can be found on neuromuscular junctions.[11] Syncoilin is also enriched in areas such as the perinuclear space and myotendinous junction. When there is a lack of either α-dystrobrevin or desmin, the expression of syncoilin is changed in order to compensate for the loss of one or both of the proteins.[12]

In addition to another intermediate filament called peripherin, syncoilin can also be found in the central nervous system and the peripheral nervous system. The spinal cord is able to express variants of the original SYNC gene into two alternate isoforms called SYNC1 and SYNC2. However, SYNC1 and SYNC2 are dominant in different nervous systems. SYNC1 is more typically found in the brain and SYNC2 is typically found in the peripheral nervous system and spinal cord.[13]

Clinical significance

Muscular diseases

When skeletal and cardiac muscle contain increased levels of syncoilin, it can often lead to disease in the muscle tissue.

Examples of diseases that syncoilin has been linked to include:

Syncoilin strongly interacts with the filament, desmin, which suggests that a mutation in syncoilin might affect the bond between desmin and the sarcolemma. This may result in desmin-related myopathy.[5] Another cause of muscular diseases is a mutation in the SYNC gene.[6]

Gastric diseases

Mutations that affect syncoilin or a lack of syncoilin can be contributing factors that lead to cellular necrosis.[3] The gene SYNC that identifies syncoilin was found to be expressed at higher levels in gastric cancer tissue than in regular gastric tissues. Within the gastric cancer tissues, the syncoilin was found primarily in the cytoplasm and the cell membrane. A recent study shows that gastric cancer tissues that have high SYNC expression reveal a strong correlation with low survival rates for the individual. More specifically, higher gene expression of SYNC in gastric cancer tissues suggests that the individual is at a more advanced stage of gastric cancer and a potentially more aggressive type subtype of gastric cancer.[14]

References

  1. ^ "SYNC - Syncoilin - Homo sapiens (Human) - SYNC gene & protein". www.uniprot.org. Retrieved 20 December 2021.
  2. ^ Newey SE, Howman EV, Ponting CP, Benson MA, Nawrotzki R, Loh NY, et al. (March 2001). "Syncoilin, a novel member of the intermediate filament superfamily that interacts with alpha-dystrobrevin in skeletal muscle". The Journal of Biological Chemistry. 276 (9): 6645–6655. doi:10.1074/jbc.M008305200. PMID 11053421.
  3. ^ a b Poon E, Howman EV, Newey SE, Davies KE (February 2002). "Association of syncoilin and desmin: linking intermediate filament proteins to the dystrophin-associated protein complex". The Journal of Biological Chemistry. 277 (5): 3433–3439. doi:10.1074/jbc.M105273200. PMID 11694502.
  4. ^ a b Kemp MW, Edwards B, Burgess M, Clarke WT, Nicholson G, Parry DA, Davies KE (March 2009). "Syncoilin isoform organization and differential expression in murine striated muscle". Journal of Structural Biology. 165 (3): 196–203. doi:10.1016/j.jsb.2008.11.002. PMID 19070665.
  5. ^ a b c d Howman EV, Sullivan N, Poon EP, Britton JE, Hilton-Jones D, Davies KE (January 2003). "Syncoilin accumulation in two patients with desmin-related myopathy". Neuromuscular Disorders. 13 (1): 42–48. doi:10.1016/S0960-8966(02)00181-5. PMID 12467731. S2CID 43131423.
  6. ^ a b c Brown SC, Torelli S, Ugo I, De Biasia F, Howman EV, Poon E, et al. (December 2005). "Syncoilin upregulation in muscle of patients with neuromuscular disease". Muscle & Nerve. 32 (6): 715–725. doi:10.1002/mus.20431. PMID 16124004. S2CID 39218012.
  7. ^ a b c d Moorwood C (October 2008). "Syncoilin, an intermediate filament-like protein linked to the dystrophin associated protein complex in skeletal muscle". Cellular and Molecular Life Sciences. 65 (19): 2957–2963. doi:10.1007/s00018-008-8306-9. PMID 18810324.
  8. ^ Zhang J, Bang ML, Gokhin DS, Lu Y, Cui L, Li X, et al. (May 2008). "Syncoilin is required for generating maximum isometric stress in skeletal muscle but dispensable for muscle cytoarchitecture". American Journal of Physiology. Cell Physiology. 294 (5): C1175–C1182. doi:10.1152/ajpcell.00049.2008. PMID 18367591.
  9. ^ a b c McCullagh KJ, Edwards B, Kemp MW, Giles LC, Burgess M, Davies KE (May 2008). "Analysis of skeletal muscle function in the C57BL6/SV129 syncoilin knockout mouse". Mammalian Genome. 19 (5): 339–351. doi:10.1007/s00335-008-9120-2. PMC 2515546. PMID 18594912.
  10. ^ a b Van Rossen E, Liu Z, Blijweert D, Eysackers N, Mannaerts I, Schroyen B, et al. (January 2014). "Syncoilin is an intermediate filament protein in activated hepatic stellate cells". Histochemistry and Cell Biology. 141 (1): 85–99. doi:10.1007/s00418-013-1142-5. PMID 24043511.
  11. ^ Blake, Derek J; Martin-Rendon, Enca (2002-07-01). "Intermediate Filaments and the Function of the Dystrophin–Protein Complex". Trends in Cardiovascular Medicine. 12 (5): 224–228. doi:10.1016/S1050-1738(02)00166-4. ISSN 1050-1738.
  12. ^ McCullagh KJ, Edwards B, Poon E, Lovering RM, Paulin D, Davies KE (December 2007). "Intermediate filament-like protein syncoilin in normal and myopathic striated muscle". Neuromuscular Disorders. 17 (11–12): 970–979. doi:10.1016/j.nmd.2007.06.004. PMID 17629480.
  13. ^ Clarke WT, Edwards B, McCullagh KJ, Kemp MW, Moorwood C, Sherman DL, et al. (August 2010). "Syncoilin modulates peripherin filament networks and is necessary for large-calibre motor neurons". Journal of Cell Science. 123 (Pt 15): 2543–2552. doi:10.1242/jcs.059113. PMC 2908046. PMID 20587592.
  14. ^ Wang D, Deng L, Xu X, Ji Y, Jiao Z (March 2021). "Elevated SYNC Expression Is Associated with Gastric Tumorigenesis and Infiltration of M2-Polarized Macrophages in the Gastric Tumor Immune Microenvironment". Genetic Testing and Molecular Biomarkers. 25 (3): 236–246. doi:10.1089/gtmb.2020.0131. PMID 33734892.
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