Group:MUZIC:Myozenin

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[[Image:FATZ.png|550px|left|thumb|FATZ-1 regions]]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.[http://www.uniprot.org/uniprot/Q9NP98][http://www.uniprot.org/uniprot/Q9NPC6][http://www.uniprot.org/uniprot/Q8TDC0]
[[Image:FATZ.png|550px|left|thumb|FATZ-1 regions]]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.[http://www.uniprot.org/uniprot/Q9NP98][http://www.uniprot.org/uniprot/Q9NPC6][http://www.uniprot.org/uniprot/Q8TDC0]
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),<ref>PMID: 11171996</ref>; although there is no tridimensional model for the structure of any of the isoforms.
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),<ref>PMID: 11171996</ref>; although there is no tridimensional model for the structure of any of the isoforms.
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== FATZ interactions and their physiological role==
== FATZ interactions and their physiological role==

Revision as of 10:38, 5 July 2011

Contents

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.png
FATZ-1 regions
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

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]

Image:FATZbinding3.jpg
Mapping of binding regions on FATZ
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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