Group:MUZIC:Myozenin

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[[Image:FATZ_binding_map.jpg|550px|left|thumb|Binding regions on FATZ proteins]]The three isoforms of FATZ have a plethora of interacting partners which are additionally shared by all of them. As shown by the figure on the right, they interact with several Z-disc proteins. For instance: α-actinin-2, filamin-C, myotilin, telethonin, calcineurin and ZASP/Cypher (in general the Enigma protein family) <ref>PMID: 11171996</ref><ref>PMID: 11842093</ref><ref>PMID: 19047374</ref><ref>PMID: 16076904</ref><ref>PMID: 11114196</ref><ref>PMID: 10984498</ref>. In general, those interactions and their binding regions were found by yeast two-hybrid assays, co-immunoprecipitation, and pull down assays.
[[Image:FATZ_binding_map.jpg|550px|left|thumb|Binding regions on FATZ proteins]]The three isoforms of FATZ have a plethora of interacting partners which are additionally shared by all of them. As shown by the figure on the right, they interact with several Z-disc proteins. For instance: α-actinin-2, filamin-C, myotilin, telethonin, calcineurin and ZASP/Cypher (in general the Enigma protein family) <ref>PMID: 11171996</ref><ref>PMID: 11842093</ref><ref>PMID: 19047374</ref><ref>PMID: 16076904</ref><ref>PMID: 11114196</ref><ref>PMID: 10984498</ref>. In general, those interactions and their binding regions were found by yeast two-hybrid assays, co-immunoprecipitation, and pull down assays.
-
The interaction of FATZ-1 with α-actinin-2 was reported simultaneously by three different groups <ref>PMID: 10984498</ref><ref>PMID: 11171996 </ref><ref>PMID: 11842093</ref>. It was documented with the three isoforms of FATZ, which showed their binding regions within the CD2. Furthermore, the data suggested a binding interface on α-actinin-2 starting in the middle of the SR2, followed by the SR3 and the SR4. FATZ-1, α-actinin-2 and myotilin appeared in premyofibrils, when there is no Z-disc but a small structure called Z-body. In addition, the complexes FATZ-1::α-actinin-2, FATZ-1::myotilin and myotilin::α-actinin-2 were also observed in that early stages. In contrast, telethonin localized to the Z-disc in later stages and the complex FATZ-1::telethonin was only observed in mature myofibrils. These findings suggested that the interactions of FATZ-1 with α-actinin-2 and myotilin are very important for the initiation of the Z-disc assembling. Besides, it was hypothesized that FATZ-1 should undergone conformational changes during myofibrilogenesis that determines the interaction with telethonin; therefore, its incorporation to the the Z-disc <ref> PMID: 15810059 </ref>. FATZ-1 has been suggested to perform other functions, like bridging filamin-C and α-actinin-2. However, it was reported in a competitive binding assay that α-actinin-2 displaces filamin-C form FATZ-1. Therefore, it is still an open question whether a ternary complex could exist and what its physiological role would be <ref>PMID: 11171996</ref>.
+
The interaction of FATZ-1 with α-actinin-2 was reported simultaneously by three different groups <ref>PMID: 10984498</ref><ref>PMID: 11171996 </ref><ref>PMID: 11842093</ref>. It was documented with the three isoforms of FATZ, which showed their binding regions within the CD2. Furthermore, the data suggested a binding interface on α-actinin-2 starting in the middle of the SR2, followed by the SR3 and the SR4. FATZ-1, α-actinin-2 and myotilin appeared in premyofibrils, when there is no Z-disc but a small structure called Z-body. In addition, the complexes FATZ-1::α-actinin-2, FATZ-1::myotilin and myotilin::α-actinin-2 were also observed in that early stages. In contrast, telethonin localized to the Z-disc in later stages and the complex FATZ-1::telethonin was only observed in mature myofibrils. These findings suggested that the interactions of FATZ-1 with α-actinin-2 and myotilin are very important for the initiation of the Z-disc assembling. Besides, it was hypothesized that FATZ-1 should undergone conformational changes during myofibrilogenesis which determines the interaction with telethonin; thus, the telethonin incorporation to the the Z-disc <ref> PMID: 15810059 </ref>. It was suggested that FATZ-1 performs other functions, like bridging filamin-C and α-actinin-2. However, it was reported in a competitive binding assay that α-actinin-2 displaces filamin-C from FATZ-1. Therefore, it is still an open question whether a ternary complex could exist and what its physiological role would be <ref>PMID: 11171996</ref>.
Both isoforms, FATZ-1 and FATZ-2 were shown to be negative regulators of the calcineurin/NFAT signaling pathway in striated muscle. In skeletal muscle, the activation of calcineurin/NFAT specifically determines the switch to the phenotype slow-twitch fibers. FATZ-1 is specifically expressed in fast-twitch fibers and its absence was seen to switch the skeletal muscle composition toward slow-twitch fiber0. This was associated with an increase in the activity of the calcineurin/NFAT signaling pathway, consequently a major number of oxidative fibers, and less fatigue of the mutant vs the wild type mice during long endurance exercise . Therefore, it was concluded that FATZ-1 interaction with calcineurin defines the fiber type composition of skeletal muscle and the response to exercise performance <ref>PMID: 18846255</ref>. The isoform FATZ-2 also controls the activity of calcineurin in cardiac fibers; therefore, it is an important protein to maintain the homeostasis of cardiac fibers subjected to pressure overload via the calcineurin/NFAT signalling pathway <ref>PMID: 15543153</ref>.
Both isoforms, FATZ-1 and FATZ-2 were shown to be negative regulators of the calcineurin/NFAT signaling pathway in striated muscle. In skeletal muscle, the activation of calcineurin/NFAT specifically determines the switch to the phenotype slow-twitch fibers. FATZ-1 is specifically expressed in fast-twitch fibers and its absence was seen to switch the skeletal muscle composition toward slow-twitch fiber0. This was associated with an increase in the activity of the calcineurin/NFAT signaling pathway, consequently a major number of oxidative fibers, and less fatigue of the mutant vs the wild type mice during long endurance exercise . Therefore, it was concluded that FATZ-1 interaction with calcineurin defines the fiber type composition of skeletal muscle and the response to exercise performance <ref>PMID: 18846255</ref>. The isoform FATZ-2 also controls the activity of calcineurin in cardiac fibers; therefore, it is an important protein to maintain the homeostasis of cardiac fibers subjected to pressure overload via the calcineurin/NFAT signalling pathway <ref>PMID: 15543153</ref>.

Revision as of 11:04, 12 December 2012

Contents

Introduction

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, that is also known as Myozenin or Calsarcin, is mainly localized in the Z-disc, although recently it has been described that FATZ-2 appears in cardiac nuclei. [2] The expression of the three isoforms has been shown to be fibre type specific. For instance, FATZ-1 and FATZ-3 are exclusively expressed in skeletal muscle fast-twitch fibres while FATZ-2 is expressed in cardiac and slow-twitch fibres [3][4]. FATZ proteins have multiple binding partners in the Z-disc, which involve them in different functions like the Z-disc formation and maintenance or in signaling pathways like the calcineurin/NFAT [5]. Therefore, the FATZ protein family could be seen as one example of Z-disc proteins where signalling and structural support converge.

Sequence Annotation

The sequence annotation of FATZ-1 shows the sequence conservation profile among the three isoforms
The sequence annotation of FATZ-1 shows the sequence conservation profile among the three isoforms
The sequence annotation of FATZ-1 is related to the sequence conservation profile among the three isoforms, which share well conserved N-terminal and C-terminal regions. Therefore, the N-terminal of FATZ-1 was named conserved domain 1 (CD1, 1-75aa) and its C-terminal conserved domain 2 (CD2, 163-299aa). Both regions are connected by a stretch of amino acids with a 39.5% of glycine; consequently, this region was named the glycine rich region (GRR, 75-162aa)[6] Q9NP98. Although the N-terminal and C-terminal regions of the other two isoforms could be also named CD1 and CD2 no such sequence annotations exist in their UniProtKB entries Q9NPC6Q8TDC0.

Function and Interactions

Binding regions on FATZ proteins
Binding regions on FATZ proteins
The three isoforms of FATZ have a plethora of interacting partners which are additionally shared by all of them. As shown by the figure on the right, they interact with several Z-disc proteins. For instance: α-actinin-2, filamin-C, myotilin, telethonin, calcineurin and ZASP/Cypher (in general the Enigma protein family) [7][8][9][10][11][12]. In general, those interactions and their binding regions were found by yeast two-hybrid assays, co-immunoprecipitation, and pull down assays.

The interaction of FATZ-1 with α-actinin-2 was reported simultaneously by three different groups [13][14][15]. It was documented with the three isoforms of FATZ, which showed their binding regions within the CD2. Furthermore, the data suggested a binding interface on α-actinin-2 starting in the middle of the SR2, followed by the SR3 and the SR4. FATZ-1, α-actinin-2 and myotilin appeared in premyofibrils, when there is no Z-disc but a small structure called Z-body. In addition, the complexes FATZ-1::α-actinin-2, FATZ-1::myotilin and myotilin::α-actinin-2 were also observed in that early stages. In contrast, telethonin localized to the Z-disc in later stages and the complex FATZ-1::telethonin was only observed in mature myofibrils. These findings suggested that the interactions of FATZ-1 with α-actinin-2 and myotilin are very important for the initiation of the Z-disc assembling. Besides, it was hypothesized that FATZ-1 should undergone conformational changes during myofibrilogenesis which determines the interaction with telethonin; thus, the telethonin incorporation to the the Z-disc [16]. It was suggested that FATZ-1 performs other functions, like bridging filamin-C and α-actinin-2. However, it was reported in a competitive binding assay that α-actinin-2 displaces filamin-C from FATZ-1. Therefore, it is still an open question whether a ternary complex could exist and what its physiological role would be [17].

Both isoforms, FATZ-1 and FATZ-2 were shown to be negative regulators of the calcineurin/NFAT signaling pathway in striated muscle. In skeletal muscle, the activation of calcineurin/NFAT specifically determines the switch to the phenotype slow-twitch fibers. FATZ-1 is specifically expressed in fast-twitch fibers and its absence was seen to switch the skeletal muscle composition toward slow-twitch fiber0. This was associated with an increase in the activity of the calcineurin/NFAT signaling pathway, consequently a major number of oxidative fibers, and less fatigue of the mutant vs the wild type mice during long endurance exercise . Therefore, it was concluded that FATZ-1 interaction with calcineurin defines the fiber type composition of skeletal muscle and the response to exercise performance [18]. The isoform FATZ-2 also controls the activity of calcineurin in cardiac fibers; therefore, it is an important protein to maintain the homeostasis of cardiac fibers subjected to pressure overload via the calcineurin/NFAT signalling pathway [19].

Pathology

It was shown that FATZ-2 KO mouse hearts subjected to pressure overload chronically activated the calcineurin/NFAT signalling pathway. In consequence, those animals showed hypertrophic hearts and developed cardiomyopathy. Moreover, the transgenic over-expression of FATZ-2 rescued the mouse hearts from angiotensin II-induced cardiac hypertrophy, which suggested that FATZ-2 could be a target gene affected in patients with the same disease [20]. Later on, the investigation of two families with clinical symptoms of hypertrophic cardiomyopathy(HCM) suggested that mutations S48P and I246M in FATZ-2 where associated with familial HCM [21]. However, another study on 438 patiens concluded that mutations in FATZ-2 were rare causes of familial HCM. [22]. Recently, a set of experiments in mice models expressing the mutants FATZ-2 S48P and I246M showed the clinical symptoms of HCM, myofibrillar disarray, and Z-disc structural abnormalities. However, no upregulation of the calcineurin/NFAT signalling pathway was observed, suggesting that HCM caused by those mutations is not associated to the inhibitory effect of FATZ-2 on calcineurin. [23].

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. ↑ 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
  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, 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
  16. ↑ 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
  17. ↑ 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
  18. ↑ Frey N, Frank D, Lippl S, Kuhn C, Kogler H, Barrientos T, Rohr C, Will R, Muller OJ, Weiler H, Bassel-Duby R, Katus HA, Olson EN. Calsarcin-2 deficiency increases exercise capacity in mice through calcineurin/NFAT activation. J Clin Invest. 2008 Nov;118(11):3598-608. doi: 10.1172/JCI36277. Epub 2008 Oct 9. PMID:18846255 doi:10.1172/JCI36277
  19. ↑ 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
  20. ↑ 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
  21. ↑ 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
  22. ↑ 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
  23. ↑ Ruggiero A, Chen SN, Lombardi R, Rodriguez G, Marian AJ. Pathogenesis of hypertrophic cardiomyopathy caused by myozenin 2 mutations is independent of calcineurin activity. Cardiovasc Res. 2012 Oct 19. PMID:22987565 doi:10.1093/cvr/cvs294

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