FLNC (gene) explained

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.[1] [2] [3] Filamin-C is mainly expressed in cardiac and skeletal muscles, and functions at Z-discs and in subsarcolemmal regions.

Structure

Filamin-C is a 290.8 kDa protein composed of 2725 amino acids.[4] [5] Filamin-C, like the ubiquitously-expressed isoform Filamin-A, have an N-terminal filamentous actin-binding domain, followed by a lengthy C-terminal self-association domain containing a series of immunoglobulin-like domains, and a membrane glycoprotein-binding domain.[6] Filamin-C interacts with γ-sarcoglycan and δ-sarcoglycan at the sarcolemma;[7] [8] myotilin and FATZ/calsarcin/myozenin at Z-lines,[9] [10] [11] [12] as well as LL5β.[13] Filamin-C has also been shown to interact with INPPL1,[14] KCND2,[15] and MAP2K4.[16]

Function

The family of Filamin proteins crosslink actin filaments into orthogonal networks in cortical cytoplasm and participate in the anchoring of membrane proteins for the actin cytoskeleton. However, the precise function of the Filamin-C isoform is still under investigation. As Filamin-C is localized mainly to striated muscle, its functions are likely specific to the specialized sarcomeric cytoskeleton present in muscle. As Filamin-C is found at both subsarcolemmal regions and at Z-lines, one plausible function of Filamin-C would be to act as a mode of communication between the membrane and the sarcomere. In skeletal muscle, Filamin-C is found at sites of core formation in skeletal myopathies,[17] and alterations in subcellular localization of Filamin-C have been exhibited in limb-girdle muscular dystrophy and Duchenne muscular dystrophy.[18]

Clinical significance

Mutations in Filamin C have been associated with human hypertrophic cardiomyopathy, dilated cardiomyopathy[19] restrictive cardiomyopathy[20] and a higher incidence of sudden cardiac death.[21] Expression of mutant protein in rat cardiac cells demonstrated that mutant Filamin C forms aggregates, which may provide a mechanistic link to the observed cardiac dysfunction.[21] Deficiency of this protein has been associated with muscle weakness.[22]

Further reading

External links

Notes and References

  1. Maestrini E, Patrosso C, Mancini M, Rivella S, Rocchi M, Repetto M, Villa A, Frattini A, Zoppè M, Vezzoni P . Mapping of two genes encoding isoforms of the actin binding protein ABP-280, a dystrophin like protein, to Xq28 and to chromosome 7 . Human Molecular Genetics . 2 . 6 . 761–6 . June 1993 . 7689010 . 10.1093/hmg/2.6.761 .
  2. Gariboldi M, Maestrini E, Canzian F, Manenti G, De Gregorio L, Rivella S, Chatterjee A, Herman GE, Archidiacono N, Antonacci R . Comparative mapping of the actin-binding protein 280 genes in human and mouse . Genomics . 21 . 2 . 428–30 . May 1994 . 8088838 . 10.1006/geno.1994.1288 .
  3. Web site: Entrez Gene: FLNC filamin C, gamma (actin binding protein 280).
  4. Web site: Protein information. © COPaKB. 2015-03-26. https://web.archive.org/web/20160304105617/http://www.heartproteome.org/copa/ProteinInfo.aspx?QType=Protein%20ID&QValue=Q14315. 2016-03-04. dead.
  5. Zong NC, Li H, Li H, Lam MP, Jimenez RC, Kim CS, Deng N, Kim AK, Choi JH, Zelaya I, Liem D, Meyer D, Odeberg J, Fang C, Lu HJ, Xu T, Weiss J, Duan H, Uhlen M, Yates JR, Apweiler R, Ge J, Hermjakob H, Ping P . Integration of cardiac proteome biology and medicine by a specialized knowledgebase . Circulation Research . 113 . 9 . 1043–53 . October 2013 . 23965338 . 4076475 . 10.1161/CIRCRESAHA.113.301151 .
  6. van der Flier A, Sonnenberg A . Structural and functional aspects of filamins . Biochimica et Biophysica Acta (BBA) - Molecular Cell Research . 1538 . 2–3 . 99–117 . April 2001 . 11336782 . 10.1016/s0167-4889(01)00072-6 . free .
  7. Guyon JR, Kudryashova E, Potts A, Dalkilic I, Brosius MA, Thompson TG, Beckmann JS, Kunkel LM, Spencer MJ . Calpain 3 cleaves filamin C and regulates its ability to interact with gamma- and delta-sarcoglycans . Muscle & Nerve . 28 . 4 . 472–83 . October 2003 . 14506720 . 10.1002/mus.10465 . 86353802 .
  8. Thompson TG, Chan YM, Hack AA, Brosius M, Rajala M, Lidov HG, McNally EM, Watkins S, Kunkel LM . Filamin 2 (FLN2): A muscle-specific sarcoglycan interacting protein . The Journal of Cell Biology . 148 . 1 . 115–26 . January 2000 . 10629222 . 3207142 . 10.1083/jcb.148.1.115 .
  9. van der Ven PF, Wiesner S, Salmikangas P, Auerbach D, Himmel M, Kempa S, Hayess K, Pacholsky D, Taivainen A, Schröder R, Carpén O, Fürst DO . Indications for a novel muscular dystrophy pathway. gamma-filamin, the muscle-specific filamin isoform, interacts with myotilin . The Journal of Cell Biology . 151 . 2 . 235–48 . October 2000 . 11038172 . 2192634 . 10.1083/jcb.151.2.235 .
  10. Takada F, Vander Woude DL, Tong HQ, Thompson TG, Watkins SC, Kunkel LM, Beggs AH . Myozenin: an alpha-actinin- and gamma-filamin-binding protein of skeletal muscle Z lines . Proceedings of the National Academy of Sciences of the United States of America . 98 . 4 . 1595–600 . February 2001 . 11171996 . 29302 . 10.1073/pnas.041609698 . free .
  11. Frey N, Olson EN . Calsarcin-3, a novel skeletal muscle-specific member of the calsarcin family, interacts with multiple Z-disc proteins . The Journal of Biological Chemistry . 277 . 16 . 13998–4004 . April 2002 . 11842093 . 10.1074/jbc.M200712200 . free .
  12. Faulkner G, Pallavicini A, Comelli A, Salamon M, Bortoletto G, Ievolella C, Trevisan S, Kojic' S, Dalla Vecchia F, Laveder P, Valle G, Lanfranchi G . FATZ, a filamin-, actinin-, and telethonin-binding protein of the Z-disc of skeletal muscle . The Journal of Biological Chemistry . 275 . 52 . 41234–42 . December 2000 . 10984498 . 10.1074/jbc.M007493200 . free .
  13. Paranavitane V, Coadwell WJ, Eguinoa A, Hawkins PT, Stephens L . LL5beta is a phosphatidylinositol (3,4,5)-trisphosphate sensor that can bind the cytoskeletal adaptor, gamma-filamin . The Journal of Biological Chemistry . 278 . 2 . 1328–35 . January 2003 . 12376540 . 10.1074/jbc.M208352200 . free .
  14. Dyson JM, O'Malley CJ, Becanovic J, Munday AD, Berndt MC, Coghill ID, Nandurkar HH, Ooms LM, Mitchell CA . The SH2-containing inositol polyphosphate 5-phosphatase, SHIP-2, binds filamin and regulates submembraneous actin . The Journal of Cell Biology . 155 . 6 . 1065–79 . December 2001 . 11739414 . 2150887 . 10.1083/jcb.200104005 .
  15. Petrecca K, Miller DM, Shrier A . Localization and enhanced current density of the Kv4.2 potassium channel by interaction with the actin-binding protein filamin . The Journal of Neuroscience . 20 . 23 . 8736–44 . December 2000 . 11102480 . 10.1523/JNEUROSCI.20-23-08736.2000 . 6773047 . free .
  16. Marti A, Luo Z, Cunningham C, Ohta Y, Hartwig J, Stossel TP, Kyriakis JM, Avruch J . Actin-binding protein-280 binds the stress-activated protein kinase (SAPK) activator SEK-1 and is required for tumor necrosis factor-alpha activation of SAPK in melanoma cells . The Journal of Biological Chemistry . 272 . 5 . 2620–8 . January 1997 . 9006895 . 10.1074/jbc.272.5.2620 . free .
  17. Bönnemann CG, Thompson TG, van der Ven PF, Goebel HH, Warlo I, Vollmers B, Reimann J, Herms J, Gautel M, Takada F, Beggs AH, Fürst DO, Kunkel LM, Hanefeld F, Schröder R . Filamin C accumulation is a strong but nonspecific immunohistochemical marker of core formation in muscle . Journal of the Neurological Sciences . 206 . 1 . 71–8 . January 2003 . 12480088 . 10.1016/s0022-510x(02)00341-6 . 15662067 .
  18. Thompson TG, Chan YM, Hack AA, Brosius M, Rajala M, Lidov HG, McNally EM, Watkins S, Kunkel LM . Filamin 2 (FLN2): A muscle-specific sarcoglycan interacting protein . The Journal of Cell Biology . 148 . 1 . 115–26 . January 2000 . 10629222 . 3207142 . 10.1083/jcb.148.1.115 .
  19. Verdonschot . A mutation update for the FLNC gene in myopathies and cardiomyopathies. . Human Mutation . Jun 2020 . 41 . 6 . 1091–111 . 10.1002/humu.24004. 32112656 . 7318287 . free .
  20. Brodehl A, Ferrier RA, Hamilton SJ, Greenway SC, Brundler MA, Yu W, Gibson WT, McKinnon ML, McGillivray B, Alvarez N, Giuffre M, Schwartzentruber J, Gerull B, ((FORGE Canada Consortium)) . Mutations in FLNC are Associated with Familial Restrictive Cardiomyopathy . Human Mutation . 37 . 3 . 269–79 . 2016 . 26666891 . 10.1002/humu.22942 . 35455240 . free .
  21. Valdés-Mas R, Gutiérrez-Fernández A, Gómez J, Coto E, Astudillo A, Puente DA, Reguero JR, Álvarez V, Morís C, León D, Martín M, Puente XS, López-Otín C . Mutations in filamin C cause a new form of familial hypertrophic cardiomyopathy . Nature Communications . 5 . 5326 . October 2014 . 25351925 . 10.1038/ncomms6326 . 2014NatCo...5.5326V . free .
  22. Guergueltcheva V, Peeters K, Baets J, Ceuterick-de Groote C, Martin JJ, Suls A, De Vriendt E, Mihaylova V, Chamova T, Almeida-Souza L, Ydens E, Tzekov C, Hadjidekov G, Gospodinova M, Storm K, Reyniers E, Bichev S, van der Ven PF, Fürst DO, Mitev V, Lochmüller H, Timmerman V, Tournev I, De Jonghe P, Jordanova A . Distal myopathy with upper limb predominance caused by filamin C haploinsufficiency . Neurology . 77 . 24 . 2105–14 . December 2011 . 22131542 . 10.1212/WNL.0b013e31823dc51e . 10733187 .

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