Group:MUZIC:Myozenin

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FATZ/Myozenin/Calsarcin protein family

The filamin-C α-actinin telethonin Z-disc binding protein (FATZ) is a protein family of three isoforms: FATZ-1, FATZ-2, FATZ-3, which are expressed in muscle cells.[1] This protein family (also known as Myozenin or Calsarcin) is mainly localized in the Z-disc, although recently it has been described that FATZ-2 was found in cardiac nuclei. [2] The expression of the three isoforms has been shown to be fibre type specific as for instance: the members FATZ-1 and FATZ-3 are highly expressed in skeletal muscle fast twitch fibres while FATZ-2 is predominantly expressed in cardiac muscle slow-twitch fibres.[3][4] Nevertheless, the three isoforms seems to have redundant function since all the three are sharing the same binding partners. Due to its Z-disc localization and multiple binding partners, FATZ proteins can be considered as an adaptor molecule that support and maintains the Z-disc architecture. But on the other hand, FATZ-2 has been shown to be a member of a signalling pathway controlling the cell response to pressure overload[5]. Therefore, the FATZ protein family could be seen as one example of Z-disc proteins where signalling and structural support converge.

Sequence Annotation

Image:FATZ-I.jpg
FATZ-1 annotated regions accordingly to secondary elements prediction
There is not prediction of canonical domains in the tertiary structure of FATZ proteins, but for all of them there is a glycine rich region in the middle of the sequence.[1][2][3]

Based on the prediction of secondary elements, it has been identified three regions on the sequence of FATZ-1: N-terminal CD1 (1-75), glycine rich region (GRR, 75-171) and C-terminal CD2 (172-299),[6]; although there is no tridimensional model for the structure of any of the isoforms.


FATZ interactions and their physiological role

Image:FATZbinding3.jpg
Mapping of binding regions on FATZ proteins
Different interacting partners of FATZ proteins have been characterized by cellular and biochemical approaches. Screenings of yeast two-hybrid assays allowed identifying interactions with other Z-disc proteins as α-actinin-2, filamin-C, myotilin, telethonin, calcineurin and ZASP/Cypher( in general Enigma family protein).[7][8][9][10][11][12].

At the moment it is though that interaction with α-actinin-2, filamin-C, myotilin, telethonin and ZASP contributes to maintain the Z-disc scaffold. Although is worth mentioning that it has been suggested to play some role in myofibril formation, since FATZ-1 has been seen in premyofibrils as α-actinin-2, filamin-C, myotilin, while titin and telethonin has been seen in more advanced stages.[13] Most of the mapping of the binding regions where done by screening dna libraries with the yeast two-hybrid assays and furthermore confirmed by co-immunoprecipitation or pull down assays. Many interacting partners have their binding sites in the C-terminal of FATZs while others in the N-terminal region. In some cases as for a-actinin-2 and filamin-C, there is competitively binding, even though the physiological relevance of such competition is not yet understood[14]. Moreover, FATZ-2 has been described as a negative modulator of the phosphatase activity of calcineurin. [15] <!—link to calcineurin page-->. Therefore by preventing dephosphorylation activity of calcineurin, this interaction involves FATZ protein family in a signalling pathway controlling the cell response to pressure overload.

Association of hypertrophic cardiomyopathy with FATZ-2

In experimental models, it has been shown that the absence of FATZ-2 led to up-regulation of calcineurin phosphatase activity and cellular proliferation, thereby inducing hypertrophic cardiomyopathy. [16] Moreover, the study of families this disease has suggested that mutations X and Y in FAT-2 where associated with the pathology. [17]Nevertheless, another study has also shown that there was no correlation between the suggested mutations and the disease. [18]. Given that, whether FATZ-2 is a marker of hypertrophic cardiomyopathy or not is still under discussion and more studies shall be done to clearly define its physiological role in cardiomyocyte.

References

  1. ↑ 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. J Biol Chem. 2000 Dec 29;275(52):41234-42. PMID:10984498 doi:10.1074/jbc.M007493200
  2. ↑ Paulsson AK, Franklin S, Mitchell-Jordan SA, Ren S, Wang Y, Vondriska TM. Post-translational regulation of calsarcin-1 during pressure overload-induced cardiac hypertrophy. J Mol Cell Cardiol. 2010 Jun;48(6):1206-14. Epub 2010 Feb 17. PMID:20170660 doi:10.1016/j.yjmcc.2010.02.009
  3. ↑ Frey N, Richardson JA, Olson EN. Calsarcins, a novel family of sarcomeric calcineurin-binding proteins. Proc Natl Acad Sci U S A. 2000 Dec 19;97(26):14632-7. PMID:11114196 doi:10.1073/pnas.260501097
  4. ↑ Frey N, Olson EN. Calsarcin-3, a novel skeletal muscle-specific member of the calsarcin family, interacts with multiple Z-disc proteins. J Biol Chem. 2002 Apr 19;277(16):13998-4004. Epub 2002 Feb 12. PMID:11842093 doi:10.1074/jbc.M200712200
  5. ↑ Frey N, Barrientos T, Shelton JM, Frank D, Rutten H, Gehring D, Kuhn C, Lutz M, Rothermel B, Bassel-Duby R, Richardson JA, Katus HA, Hill JA, Olson EN. Mice lacking calsarcin-1 are sensitized to calcineurin signaling and show accelerated cardiomyopathy in response to pathological biomechanical stress. Nat Med. 2004 Dec;10(12):1336-43. Epub 2004 Nov 14. PMID:15543153 doi:nm1132
  6. ↑ 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. Proc Natl Acad Sci U S A. 2001 Feb 13;98(4):1595-600. Epub 2001 Feb 6. PMID:11171996 doi:10.1073/pnas.041609698
  7. ↑ 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. Proc Natl Acad Sci U S A. 2001 Feb 13;98(4):1595-600. Epub 2001 Feb 6. PMID:11171996 doi:10.1073/pnas.041609698
  8. ↑ Frey N, Olson EN. Calsarcin-3, a novel skeletal muscle-specific member of the calsarcin family, interacts with multiple Z-disc proteins. J Biol Chem. 2002 Apr 19;277(16):13998-4004. Epub 2002 Feb 12. PMID:11842093 doi:10.1074/jbc.M200712200
  9. ↑ von Nandelstadh P, Ismail M, Gardin C, Suila H, Zara I, Belgrano A, Valle G, Carpen O, Faulkner G. A class III PDZ binding motif in the myotilin and FATZ families binds enigma family proteins: a common link for Z-disc myopathies. Mol Cell Biol. 2009 Feb;29(3):822-34. Epub 2008 Dec 1. PMID:19047374 doi:10.1128/MCB.01454-08
  10. ↑ Gontier Y, Taivainen A, Fontao L, Sonnenberg A, van der Flier A, Carpen O, Faulkner G, Borradori L. The Z-disc proteins myotilin and FATZ-1 interact with each other and are connected to the sarcolemma via muscle-specific filamins. J Cell Sci. 2005 Aug 15;118(Pt 16):3739-49. Epub 2005 Aug 2. PMID:16076904 doi:10.1242/jcs.02484
  11. ↑ Frey N, Richardson JA, Olson EN. Calsarcins, a novel family of sarcomeric calcineurin-binding proteins. Proc Natl Acad Sci U S A. 2000 Dec 19;97(26):14632-7. PMID:11114196 doi:10.1073/pnas.260501097
  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. J Biol Chem. 2000 Dec 29;275(52):41234-42. PMID:10984498 doi:10.1074/jbc.M007493200
  13. ↑ Wang J, Shaner N, Mittal B, Zhou Q, Chen J, Sanger JM, Sanger JW. Dynamics of Z-band based proteins in developing skeletal muscle cells. Cell Motil Cytoskeleton. 2005 May;61(1):34-48. PMID:15810059 doi:10.1002/cm.20063
  14. ↑ 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. Proc Natl Acad Sci U S A. 2001 Feb 13;98(4):1595-600. Epub 2001 Feb 6. PMID:11171996 doi:10.1073/pnas.041609698
  15. ↑ Frey N, Barrientos T, Shelton JM, Frank D, Rutten H, Gehring D, Kuhn C, Lutz M, Rothermel B, Bassel-Duby R, Richardson JA, Katus HA, Hill JA, Olson EN. Mice lacking calsarcin-1 are sensitized to calcineurin signaling and show accelerated cardiomyopathy in response to pathological biomechanical stress. Nat Med. 2004 Dec;10(12):1336-43. Epub 2004 Nov 14. PMID:15543153 doi:nm1132
  16. ↑ Frey N, Barrientos T, Shelton JM, Frank D, Rutten H, Gehring D, Kuhn C, Lutz M, Rothermel B, Bassel-Duby R, Richardson JA, Katus HA, Hill JA, Olson EN. Mice lacking calsarcin-1 are sensitized to calcineurin signaling and show accelerated cardiomyopathy in response to pathological biomechanical stress. Nat Med. 2004 Dec;10(12):1336-43. Epub 2004 Nov 14. PMID:15543153 doi:nm1132
  17. ↑ Osio A, Tan L, Chen SN, Lombardi R, Nagueh SF, Shete S, Roberts R, Willerson JT, Marian AJ. Myozenin 2 is a novel gene for human hypertrophic cardiomyopathy. Circ Res. 2007 Mar 30;100(6):766-8. Epub 2007 Mar 8. PMID:17347475 doi:10.1161/01.RES.0000263008.66799.aa
  18. ↑ Posch MG, Thiemann L, Tomasov P, Veselka J, Cardim N, Garcia-Castro M, Coto E, Perrot A, Geier C, Dietz R, Haverkamp W, Ozcelik C. Sequence analysis of myozenin 2 in 438 European patients with familial hypertrophic cardiomyopathy. Med Sci Monit. 2008 Jul;14(7):CR372-4. PMID:18591919

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